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Flashcards in Biochemistry - First Aid Deck (609):
1

DNA exists in the...

condensed, chromatin form in order to fit into the nucleus.

2

Negatively charged DNA loops...

twice around positively charged histone octamer to form a nucleosome "bead".

3

Histones are rich in...

the amino acids lysine and arginine.

4

H1 binds to the...

nucleosome and to linker DNA, thereby stabilizing the chromatin fiber.

5

In mitosis, DNA will...

condense to form chromosomes.

6

DNA and histone synthesis occurs during...

S phase.

7

The only histone that is not in the DNA core is...

H1.

8

Heterochromatin is..

condensed, transcriptionally inactive, sterically inaccessibl.e.

9

Euchromatin is...

less condensed, transcriptionally active and sterically accessible.

10

In DNA replications, the template strand cytosine and adenine are...

methylated which allows mismatch repair enzymes to distinguish between old and new strands in prokaryotes.

11

DNA methylation at CpG islands acts to...

repress transcription.

12

Histone methylation usually...

represses DNA transcription.

13

Histone acetylation acts to...

relax DNA coiling, allowing for transcription.

14

Purines

Adenine and Guanine; 2 rings

15

Pyrimidines

Cytosine and Thymine; 1 ring

(thymine has a methyl)

16

Deamination of cytosine makes...

uracil. Uracil is found in RNA; thymine in DNA.

17

The G-C bond has...

3 H bonds and is stronger than the A-T bond which has 2. Increased G-C content leads to increased melting temp of DNA.

18

Amino acids necessary for purine synthesis

Glycine
Aspartate
Glutamine

19

Nucleoside

base + deoxyribose

20

Nucleotide

base + deoxyribose + phoshpate

(linked by 3'5' phosphodiester bond)

21

Purines de novo synthesis

start with sugar + phosphate (PRPP); add base

22

Pyrimidine de novo synthesis

make temporary base (orotic acid); add sugar and phosphate; modify base

23

Ribonucleotides are synthesized...

first and are converted to deoxyribonucleotides by ribonucleotide reductase.

24

Carbamoyl phosphate is involved in 2 metabolic pathways:

de novo pyrimidine synthesis and the urea cycle.

25

Various antineoplastic and antibiotic drugs function by interfering with nucleotide synthesis:

1. Leflunomide
2. Mycophenolate and Ribavirin
3. Hydroxyurea
4. 6-Mercaptopurine
5. 5-Fluorouracil
6. Methotrexate, trimethoprim and pyrimethamine

26

Leflunomide MOA

inhibits dihydroorotate dehydrogenase

27

Mycophenolate and Ribavirin inhibit...

IMP dehydrogenase

28

Hydroxyurea inhibits...

ribonucleotide reductase.

29

6-MP and its prodrug Azathioprine inhibit...

de novo purine synthesis.

30

5-FU inhibits...

thymidylate synthatse.

31

Methotrexate, Trimethoprim, and Pyrimethamine inhibit...

dihydrofolate reductase in humans, bacteria, and protozoa respectively.

32

Adenosine deaminase deficiency leads to excess...

ATP and dATP imbalance of the nucleotide pool via feedback inhibition of ribonucleotide reductase which prevents DNA synthesis and thus decreases lymphocyte count.

33

Adenosine deaminase deficiency is one of the major causes of...

SCID.

34

Lesch-Nyhan Syndrome has...

defective purine salvage due to absent HGPRT, which converts hypoxanthine to IMP and guanine to GMP.

35

Lesch-Nyhan Syndrome results in...

excess uric acid production and de novo purine synthesis.

36

Findings of Lesch-Nyhan

-intellectual disability
-self-mutilation
-aggression
-hyperuricemia
-gout
-dystonia

37

Treatment for Lesch-Nyhan

Allopurinol (or Febuxostat)

38

Most amino acids are coded by multiple codons (degenerate/redundant) except...

methionine and tryptophan which are only encoded by 1.

39

In both prokaryotes and eukaryotes, DNA replication is...

semiconservative and involves both continuous and discontinous (Okazaki framgent) synthesis.

40

The origin of replication is the...

particular consensus sequence of base pairs in the genome where DNA replication begins. May be single (prokaryotes) or multiple (eukaryotes).

41

The replication fork is the...

Y-shaped region along the DNA template where leading and lagging strand are synthesized.

42

Helicase acts to..

unwind DNA template at the replication fork.

43

Single-stranded binding proteins...

prevent strands from reannealing.

44

DNA topoisomerases create...

a single-or double-stranded break in the helix to add or remove supercoils.

45

Primase makes...

an RNA primer on which DNA polymerase III can initiate replication.

46

DNA polymerase III is only...

prokaryotic. It elongates the leading strand by adding deoxynucleotides to the 3' end. It elongastes the lagging strand until it reaches the primer of the preceding fragment.

(5' to 3' synthesis)

47

DNA polymerase III has...

3' to 5' exonuclease activity that "proofreads" each added nucleotide.

48

DNA polymerase I is only...

prokaryotic. It degrades RNA primer and replaces it with DNA.

49

DNA ligase catalyzes...

the formation of a phosphodiester bond within a strand of double-segmented DNA (joins Okazaki fragments).

50

Telomerase is an...

RNA dependent DNA polymerase taht adds DNA to 3' ends of chromosomes to avoid loss of genetic material with every duplication.

51

Silent mutation

nucleotide substituion but codes for the same (synonymous) amino acid; often base change in the 3rd position of the codon (tRNA wobble)

52

Missense mutation

nucleotide substitution resulting in changed amino acid (called conservative if the new amino acid is similar in chemical structure)

(ex. sickle cell disease)

53

Nonsense mutation

nucleotide substitution resulting in an early stop codon

54

Frameshift mutation

deletion or insertion of a number of nucletoides (not divisible by 3), resulting in misreading of all nucleotides downstream, usually resulting in a truncated, nonfunctional protein

55

Nucleotide excision repair

specific endonucleases release the oligonucleotide-containing damaged bases; DNA polymerase and ligase fill and reseal the gap

56

Nucleotide excision repair repairs...

bulky helix-distorting lesions.

57

Nucleotide excision repair is defective in...

xeroderma pigmentosum, which prevents repair of pyrimidine dimers because of UV light exposure.

58

Base excision repair

base-specific glycosylase recognizes altered base and creates AP site; one or more nucleotides are removed by AP-endonuclease, which cleaves the 5' end; lyase cleaves the 3' end; DNA polymerase-beta fills the gap and DNA ligase seals it

59

Base excision repair is important in the repair of...

spontaneous/toxic deamination.

60

Mismatch repair

newly synthesized strand is recognized, mismatched nucleotides are removed and the gap is filled and resealed

61

Mismatch repair is defective in...

HNPCC (hereditary nonpolyposis colorectal cancer).

62

Nonhomologous end joining brings together...

2 ends of DNA fragments to repair double-stranded breaks.

63

Nonhomologous end joining is mutated in...

ataxia telangiectasia.

64

DNA and RNA are both synthesized...

5' to 3'. The 5' end of the incoming nucleotide bears the triphosphate (energy source for the bond).

65

Protein synthesis is...

N-terminus to C-terminus.

66

mRNA is read...

5' to 3'.

67

The target of the 3' hydroxyl attack is...

the triphosphate bond.

68

Drugs blocking DNA replication often have...

modified 3' OH, preventing addition of the next nucleotide (chain termination).

69

mRNA start codon

AUG. In eukaryotes, AUG codes for methionine. In prokaryotes, it codes for f-met.

70

mRNA stop codons

UGA
UAA
UAG

71

The promoter is the site where...

RNA polymerase and multiple other transcription factors bind to DNA upstream from gene locus (an AT-rich upstream sequence with TATA and CAAT boxes).

72

Promoter mutation commonly results in...

dramatic decrease in the level of gene transcription.

73

Enhancer is a...

stretch of DNA that alters gene expression by binding transcription factors.

74

Silencer is the...

site where negative regulators bind.

75

RNA polymerase I makes..

rRNA (most numerous RNA).

76

RNA polymerase II makes...

mRNA (largest RNA).

77

RNA polymerase III makes...

tRNA (smallest RNA).

78

RNA polymerases do not have...

proofreading function but they can initiate chains.

79

Prokaryotes only have one...

RNA polymerase that makes all 3 kinds of RNA.

80

alpha-amanitin found in...

Amanita phalloides (death cap mushrooms) inhibits RNA polymerase II and causes severe hepatotoxicity.

81

The initial RNA transcript is called...

heterogenous nuclear RNA (hnRNA) and it is then modified to become mRNA.

82

The following processes occur in the nucleus following transcription of hnRNA:

1. capping of 5' end (addition of 7-methylguanosine cap)
2. polyadenylation of 3' end (w/ about 200 As)
3. splicing out of introns

(now it is mRNA)

83

mRNA is transported...

out of the nuclues into the cytosol, where it is translated.

84

mRNA quality control occurs at...

cytoplasmic P-bodies, which contain exonucleases, decapping enzymes, and microRNAs.

85

Splicing of pre-mRNA (3 steps)

1. primary transcript combines with small nuclear ribonucleoproteins (snRNPs) and other proteins to form the spliceosome
2. lariat-shaped (looped) intermediate is generated
3. lariat is released to precisely remove intron and join 2 exons.

86

Antibodies to the spliceosomal snRLNPs (anti-Smith antibodies) are highly specific for...

SLE.

87

Anti-U1 RNp antibodies are highly associated with...

mixed connective tissue disease.

88

Exons contain...

the actual genetic info coding for protein. Introns are intervening noncoding segments of DNA.

89

Different exons are frequently...

combined by alternative splicing to produce a larger number of unique proteins.

90

Abnormal splicing variants are implicated in...

oncogenesis and beta-thalassemia, etc.

91

tRNA Structure

-75-90 nucleotides
-secondary structure
-cloverleaf form
-anticodon end is opposite 3' aminoacyl end

92

All tRNAs have CCA at...

the 3' end along with a high percentage of chemically modified bases. The amino acid is covalently boudn to the 3' end.

93

T-arm of tRNA

contains the thymine, pseudouridine, cytosine sequence necessary for tRNA-ribosome binding

94

D-arm of tRNA

contains dihydrouracil residues necessary for tRNA recognition by the correct aminoacyl-tRNA synthetase

95

Acceptor stem of tRNA

the 3' CCA is the amino acid acceptor site

96

Aminoacyl-tRNA synthetase (1/amino acid; matchmaker; uses ATP) scrutinizes...

amino acid before and after it binds tRNA. If incorrect, the bond is hydrolyzed.

97

The amino acid-tRNA bond has nergy for..

formation of a peptide bond.

98

A mischarged tRNA reads...

the usual codon but inserts the wrong amino acid.

99

tRNA wobble is the idea that...

accurate base pairing is required only in the first 2 nucleotide positions of an mRNA codon so codons differing in the 3rd wobble position may code for the same tRNA/amino acid.

100

3 steps of protein synthesis

1. initiation
2. elongation
3. termination

101

Protein synthesis is iniated by...

GTP hydrolysis;

102

Iniation factors help assemble...

the 40S ribosomal subunit with the initiator tRNA and are released when the mRNA and the ribosomal 60S subunit assemble with the complex.

103

Elongation

1. aminoacyl-tRNA binds to A site
2. rRNA catalyzes peptide bond formation, transfers growing polypeptide to amino acid in A site
3. ribosome advances 3 nucleotides toward 3' end of mRNA, moving peptidyl tRNA to P site

104

Termination

stop codon is reconized by release factor and completed polypeptide is released from the ribosome

105

Trimming is...

the removal of N- or C- terminal propeptides from the zymogen to generat a mature protein

106

Covalent alterations include...

phophorylation, glycosylation, hydroxylation, methylation, acetylation and ubiquitination

107

Chaperone protein

intracellular protein involved in facilitating and/or maintaining protein folding

108

Mitosis (the shortest phase of the cell cycle) incudes...

prophase, metaphase, anaphase and telophase.

109

G1 and G0 are of...

variable duration.

110

CDKs are...

consititutive and inactive.

111

Cyclins are...

regulatory proteins that control the cell cycle events; phase specific; activate CDKs.

112

Cyclin-CDK complexes must be...

activated and inactivated for cell cycle to progress.

113

Tumor suppressors p53 and hypophosphorylated Rb normally...

inhibit G1 to S progression; mutations in these genes result in unrestrained cell division (Li-Fraumeni syndrome).

114

Permanent cell types remain in...

G0, they regenerate from stem cells.

115

Examples of permanent cells

neurons
skeletal and cardiac muscle
RBCs

116

Stable (quiesent) cells enter...

G1 from G0 when stimulated.

117

Examples of stable cells include...

hepatocytes and lymphocytes.

118

Labile cells never...

goto G0; they divide rapidly with a short G1. These are the cells most affected by chemo.

119

Examples of labile cells

-bone marrow
-gut epithelium
-skin
-hair follicles
-germ cells

120

Rough endoplasmic reticulum is the site of..

syntehsis of secretory proteins and of N-linked oligosaccharide addition to proteins.

121

Nissle bodies (RER in neurons) synthesize...

peptide NTs for secretion.

122

Free ribosomes are the site of synthesis of...

cytosolic and organellar proteins.

123

Cells rich in RER are...

mucus-secreting goblet cells and antibody-secreting plasma cells.

124

Smooth endoplasmic reticulum is the site of...

steroid syntehsis and detoxification of drugs and poisons; lacks surface ribosomes.

125

Cells rich in SER include...

liver hepatocyte sand steroid hormone-producing cells of the adrenal cortex.

126

The golgi is the...

distribution center for proteins and lipids from the ER to the vesicles and plasma membrane.

127

Golgi functions (3)

1. modifies N-oligosaccharides on asparagine
2. adds O-oligosaccharides on serine and threonine
3. adds mannose-6 phosphate to proteins for trafficking to lysosomes

128

Endosomes are...

the sorting centers for material from outside the cell or from the Golgi, sending it to lysosomes for destruction or back to the membrane/Golgi for further use.

129

I-cell disease (inclusion cell disease) is an...

inherited lysosomal storage disorder with a defect in phophotransferase leading to failure of the Golgi to phophorylate mannose residues on glycoproteins. This causes proteins to be secreted extracellularly rather than delivered to lysosomes.

130

I-cell disease results in...

coarse facial features, clouded corneas, restricted joint movement, and high plasma levels of lysosomal enzymes. Often fatal in childhood.

131

Signal recognition particle (SRP) is an...

abundant, cytosolic ribonucleoprotein that traffics proteins from the ribosome to the RER.

132

Absent/dysfunctional SRP leads to...

protein accumulation in the cytosol.

133

Vesicular trafficking proteins (3)

1. COPI
2. COPII
3. Clathrin

134

COPI traffics from...

the Golgi to the Golgi (retrograde) and from the Golgi to the ER.

135

COPII traffics from...

the Golgi to the Golgi (anterograde) and from the ER to the Golgi.

136

Clatrhin traffics from...

the trans-Golgi to the lysosomes; and from plasma membrane to endosomes

137

Peroxisome is a...

membrane-enclosed organelle involved in catabolism of very long chain fatty acids, branched chain fatty acids and amino acids.

138

Proteasome is a...

barrel-shaped protein complex that degrades damaged or ubiquitin-tagged proteins.

139

Microtubules are...

cyclindrical structures composed of a helical array of polymerized heterodimers of alpha and beta tubulin. Each dimer has 2 GTP bound.

140

Microtubules are incorporated into..

flagella, cilia, and mitotic spindles and centrioles. Also involved in slow axoplasmic transport in neurons.

141

Microtbules grow...

slowly and collapse quickly.

142

Molecular motor proteins transport...

cellular cargo toward opposite ends of microtubule tracks.

(dynein, kinesin)

143

Dynein

retrograde to microtubule (+ to -)

144

Kinesin

anterograde to microtuble (- to +)

145

Drugs that act on microtubules (5)

1. Mebendazole (anti-helminthic)
2. Griseofulvin (anti-fungal)
3. Colchicine (anti-gout)
4. Vincristine/Vinblastine (anti-cancer)
5. Paclitaxel (anti-cancer)

146

Cilia structure

9 + 2 arrangement of microtubules

147

Axonemal dynein is...

ATPase that links peripheral 9 doublets and casues bending of cilium by differential sliding of doublets.

148

Kartagener Syndrome (primary ciliary dyskinesia)

immotile cilia due to a dynein arm defect.

149

Kartagener results in...

male/female infertility due to immotile sperm and dysfunctional fallopian tube cilia. Increases the risk of ectopic pregnancy.

150

Kartagener can cause...

bronchiectasis, recurrent sinusitis and situs inversus.

151

Actin and myosin are used in:

1. muscle contraction
2. microvilli
3. cytokinesis
4. adherens junction

152

Actins are...

long, structural polymers.

153

Myosins are...

dimeric, ATP-driven motor proteins that move along actins.

154

Intermediate filaments give structure and include....

vimentin
desmin
cytokeratin
lamins
glial fibrillary acid proteins (GFAPs)
neurofilaments

155

The plasma membrane is an asymmetric lipid bilayer that contains...

cholesterol, phospholipids, sphingolipids, glycolipids, and proteins.

156

Vimentin stain is for...

CT.

157

Desmin stain is for...

muscle.

158

Cytokeratin stain is for...

epithelial cells

159

GFAP is for...

neuroglia.

160

Neurofilaments stain for...

neurons.

161

The Na+/K+ ATPase is locatd in the...

plasma membrane with ATP site on the cytosolic side.

162

For each ATP consumed in the Na/K ATPase...

3 Na+ go out and 2 K+ come in.

163

Ouabain acts to...

inhibit the Na/K ATPase by binding to the K+ site.

164

Cardiac glycosides (digoxin/digitoxin) act by...

directly inhibiting the Na-K ATPase which leads to indirect inhibition of Na/Ca exchange leading to increased intracellualr calcium and increased cardiac contractility.

165

The most abundant protein in the human body is...

collagen. It is extensively modified by posttranslational modification. It organizes and strengthens ECM.

166

Type I collagen

-most common (90%)
-bone
-skin
-tendon
-dentin
-fascia
-cornea
-late wound repair

167

There is decreased production of Type I collagen in...

osteogenesis imperfecta type I.

168

Type II collagen

-cartilage
-vitreous body
-nucleus pulposus

169

Type III Cartilage

-reticulin
-skin
-blood vessels
-uterus
-fetal tissue
-granulation tissue

170

Type III collagen deficiency is...

uncommon. An example is the vascular type of Ehlers-Danos.

171

Type IV collagen

basement membrane
basal lamina
lens

172

Type IV collagen is defective in...

Alport sydnrome and is targeted by autoantibodies in goodpasture syndrome.

173

Collagen Synthesis 4 Steps

1. Synthesis (RER)
2. Hydroxylation (RER)
3. Glycosylation (RER)
4. Exocytosis
5. Proteolytic Processing (outside fibroblast)
6. Cross-linking (outside fibroblast)

174

Syntehsis of collagen

translation of collagen alpha chains (preprocollagen) - usually Gly-X-Y (proline or lysine)

175

Hydroxylation of collagen

hydroxylation of specific proline and lysine residues (requires Vitamin C; deficiency leads to scurvy)

176

Glycosylation of collagen

Glycosylation of pro-alpha-chain hydroxylysine residues and formation of procollagen via hydrogen and disulfide bonds (triple helix of 3 collagen and alpha chains)

177

Problems forming the collagen triple helix leads to...

osteogenesis imperfecta.

178

Exocytosis of collagen

exocytosis of procollagen into extracellular space

179

Proteolytic processing of collagen

cleavage of disulfide rich terminal regions of procollagen, transforming it into insoluble tropocollagen

180

Cross-linking of collagen

reinforcement of many staggered tropocollagen molecules by covalent lysine-hydroxylysine cross-linkage (by copper containing lysyl oxidase) to make collagen fibrils.

181

Problems with collagen cross-linking lead to...

Ehlers Danos.

182

Osteogenesis imperfecta is...

a genetic bone disorder (brittle) caused by many defects. The most common one being decreased production of normal collagen (AD).

183

OI manifestations include:

1. multiple fractures with minimal trauma
2. blue sclerae (due to translucency of CT over choroidal veins)
3. hearing loss (abnormal ossicles)
4. dental imperfections (due to lack of dentin)

184

Ehlers-Danos is due to...

faulty collagen synthesis, causing hyperextensible skin, tendency to bleed and hypermobile joints.

185

Ehlers-Danos may be associated with...

joint dislocation, berry/aortic aneurysms and organ rupture.

186

Hypermobility type of Ehlers-Danos

-most common
-joint instability

187

Classical Ehlers-Danos

-mutation in type V collagen
-joint and skin symptoms

188

Vascular type of Ehlers-Danos

-deficienct type III collagen
-vascular and oran rupture

189

Menkes disease is a...

CT disease caused by impaired copper absorption and transport.

190

Menkes disease leads to...

decreased activity of lysyl oxidase (copper is a necessary cofactor)

191

Menkes disease results in...

brittle, kinky hair, growth retardation and hypotonia.

192

Elastin is a...

stretchy protein within skin, lungs, large arteries, elastic ligaments, vocal cords and ligamenta flava.

193

Elastin is rich in...

proline and glycine, nonhydroxylated forms.

194

Components of elastin include...

tropoelastin with fibrillin scaffolding.

195

Cross-linking of elastin takes place...

extracelullarly and gives elastin its elastic properties.

196

Elastin is broken down by...

elastase which is normally inhibited by alpha1-antitrypsin.

197

Marfan syndrome is caused by...

a defect in fibrillin, a glycoprotein that forms a sheath aroun elastin.

198

Emphysema can be caused by...

alpha1-antitrypsin deficiency, resulting in excess elastase activity.

199

Wrinkles of aging are due to...

decreased collagen and elastin production.

200

Polymerase Chain Rxn (PCR) is a lab procedure used to...

amplify a desired fragment of DNA.

201

3 steps of PCR

1. Denaturation
2. Annealing
3. Elongation

202

PCR Denaturation

DNA is denatured by heating to generate 2 separate strands.

203

PCR Annealing

during cooling, excess premade DNA primers anneal to a specific sequence on each strand to be amplified

204

PCR Elongation

heat-stable DNA polyemerase replicates the DNA sequence following each primer

205

Agarose gel electrophoresis is used for...

size separation of PCR products (smaller molecules travel further) which can then be compared to a DNA ladder.

206

Southern blot is a...

DNA sample that is enzymatically cleaved into smaller pieces, electrophoresed on a gel and then transferred to a filter. The filter is then soaked in a denaturant and subsequently exposed to a radiolabeled DNA probe that recognizes and anneals to its complementary strand. The resulting double-stranded, labeled piece of DNA is visualized when the filter is exposed to film.

207

Northern blot is...

similar to southern blot except that an RNA sample is electrophoresed. Useful for studying mRNA levels which are reflective of gene expression.

208

Western blot is when a...

sample protein is separated via gel electrophoresis and transferred to a filter. Labeled antibody is used to bind to relevant protein.

209

The confirmatory test for HIV after positive ELISA screening is...

Western blot.

210

Southwestern blot identifies...

DNA-binding proteins (transription factors, etc) using labeled oligonucleotide probes.

211

Microarrays are when...

thousands of nucleic acid sequences are arranged in grids on glass or silicon. DNA or RNA probes are hybridized to the chip and a scanner detects the relative amounts of compementary binding.

212

Microarrays are used to...

profile gene expression levels of thousands of genes simultaneously to study certain diseases and treatments.

213

Microarrays are able to detect...

single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) for a variety of applications including genotyping, clincial genetic testing, forensic analysis, cancer mutations and genetic linkage analysis.

214

Enzyme-linked immunoabsorbent assay is used to detect...

the presence of either a specific antigen (direct) or a specific antibody in a pt's blood sample.

215

Indirect ELISA uses a...

test antigen to see if a specific antibody is present in the pt's blood; a secondary antibody is coupled to a color-generating enzyme is added to detect the 1st Ab.

216

Direct ELISA uses a...

test antibody to see if a specific antigen is present in the pt's blood; a secondary antibody coupled to a color-generating enzyme is added to detect the Ag.

217

Both the sensitivity and specificity of ELISA approach...

100% but false-positives and false-negatives do occur.

218

Fluorescence in situ hybridization (FISH) uses a...

fluorescent DNA or RNA probe that binds to specific gene site of interest on chromosomes.

219

FISH is used for...

localization of genes and direct visualization of anomalies (microdeletions) at the molecular level (when the deletion is too small to be visualzied by karyotype).

220

Steps of Cloning (5)

1. isolate eukaryotic mRNA of interest
2. expose mRNA to reverse transcriptase to produce cDNA
3. insert cDNA fragments into bacterial plasmids containing antibiotic resistance genes
4. transform recombinant plasmid into bacteria
5. surviving bacteria on antibiotic medium produce cDNA

221

Strategies of gene expression modification

1. random insertion of gene into mouse genome
2. targeted insertion or deletion of gene through homologous recombinatino with mouse gene

222

The cre-lox system can inducibly...

manipulate genes at specific developmental points (ex. to study a gene whose deletion causes embryonic death).

223

RNA interference is when...

dsRNA is synthesized that is complementary to the mRNA sequence of interest. when transfecteed into human cells, dsRNA separates and promotes degradation of target mRNA, knocking down gene expression.

224

Karyotyping is a process by which ...

metaphase chromosomes are stained, ordered and numbered according to morphology, size, arm-length ratio and banding pattern.

225

Karyotyping can be performed on a sample of...

blood, bone marrow, amniotic fluid, or placental tissue.

226

Karyotyping is used to diagnose...

chromosomal imbalances (ex. autosomal trisomies, sex chromosome disorders).

227

Codominance

both alleles contribute to the phenotype of the heterozygote
(ex. blood groups; alpha-antityrpsin deficiency)

228

Variable expressivity

phenotype varies among individuals with the same genotype

(ex. 2 pts have NF1 may have varying disease severity)

229

Incomplete penetrance

not all individuals with a mutant genotype show the mutant phenotype

(ex. BRCA 1 gene mutations do not always result in ovarian or breast cancer)

230

Pleiotropy

one gene contributes to multiple phenotypic effects

(ex. untreated PKU manifests with light skin, intellectual disability and musty body odor)

231

Loss of heterozygosity

If a pt inherits or develops a mutation in a tumor suppressor gene, the complementary allele must be deleted/mutated before cancer develops.

(this is not true of oncogenes)

Ex. Rb and the "two-hit" hypothesis

232

Dominant negative mutation

exerts a dominant effect; a heterozygote produces a nonfunctinoal altered protein that also preventsthe normal gene product from functioning

(ex. mutation of a transcription factor in its allosteric site; nonfunctinoing mutant can still bind DNA, preventing wild-type transcription factor from binding)

233

Linkage disequilibrium

tendency for certain alleles at 2 linked loci to occur together more often than expected by chance; measured in a population, not in a family

234

Mosaicism

presence of genetically distinct cell lines in the same individual; arises from mitotic errors after fertilization

235

Somatic mosaicism

mutation propagates through multiple tissues or organs

236

Gonadal mosaicism

mutation only in egg or sperm cells

237

Locus heterogeneity

mutations at different loci can produce a similar phenotype

(Ex. albinism)

238

Allelic heterogenity

different mutations in the same locuse produce the same phenotype

(ex. beta-thalassemia)

239

Heteroplasmy

presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrial inherited disease

240

Uniparental disomy is when...

an offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent.

241

Heterodisomy (heterzygous) indicates a...

meiosis I error.

242

Isodisomy (homozygous) indicates...

a meiosis II error or postzygotic chromosomal duplication of one of a pair of chromosomes and loss of the other of the original pair.

243

Consider uniparental disomy in an individual manifesting...

a recessive disorder when only one parent is a carrier.

244

If a population is in Hardy-Weinberg equilibrium and if p and q are the frequencies of separate alleles, then...

p^2 + 2pq + q^2 = 1 and p + q = 1.

245

Hardy-Weinberg law assumptions include (4):

1. no mutation occurring at the locus
2. natural selection is not occurring
3. completely random mating
4. no net migration

246

The frequency of an X-linked recessive disease in males is...

q and in females it is q^2.

247

Imprinting

At the same loci, only one allele is active; the other is inactive (imprinted/via methylation). With one allele inactivated, deletion of the active allele leads to disease.

Ex. Prader-Willi and Angelman

248

Prader-Willi Syndrome

Maternal imprinting: gene from mom is normally silent and paternal gene is deletered

249

Prader-Willi Syndrome leads to...

hyperphagia, obesity, intellectual disability, hypogonadism, and hypotonia.

250

Angelman Syndrome

Paternal imprinting: gene from dad is normally silent and maternal gene is deleted.

251

Angelman Syndrome results in...

inappropriate laughter, seizures, ataxia and intellectual disability.

252

Example of a X-linked dominant disease

Hypophosphatemic rickets: formerly known as vitamin D-resistant rickets; inherited disorder resulting in increased phosphate wasting at the proximal tubule

253

Mitochondrial inheritance is transmitted...

only through the mother. All offspring of affected mothers may show signs fo disease.

254

Mitochondrial myopathies are rare disorders that present with...

myopathy, lactic acidosis and CNS disease. Secondary to oxidative phosphorylation; "ragged red fibers" on muscle biopsy.

255

Cystic Fibrosis Genetics

autosomal recessive defect in CFTR gene on chr 7; commonly a deletion of Phe508

256

CFTR encoes...

an ATP-gated Cl- channel that secretes Cl- in the lungs and GI tract and reabsorbs Cl- in the sweat glands

257

Mutations in CFTR lead to..

misfolded protein which causes it to be retained in RER and no transported to the cell membrane causing decreased Cl- (and H2O) secretion.

258

Increased intracellular Cl- results in...

compensatory increase in Na reabsorption via epithelial Na+ channels leading to increased H2O reabsorption leading to abnormally thick mucus secreted into the lungs and GI tract.

259

Complications of Cystic Fibrosis

recurrent pulmonary infxns (pseudomonas), chronic bronchitis and bronchiectasis (reticulonodular pattern on CXR), pancreatic insufficiency, malabsorption, steatorrhea, nasal polyps and meconium ileus. Also infertility in males and fat-soluble vitamin deficiencies.

260

Treatment for Cystic Fibrosis

-N-acetylcysteine to loosen mucus plugs (cleaves disulfide bonds within mucus glycoproteins)
-dornase alfa (DNAse to clear leukocytic debris)

261

X-linked recessive disorders

-Bruton agammaglobulinemia
-Wiskott-Aldrich
-Fabry disease
-G6PD deficiency
-Ocular albinism
-Lesch-Nyhan sydnrom
-Duchenne (and Becker) muscular dystrophy
-Hunter Syndrome
-Hemophilia A and B
-Ornithine transcarbamylase deficiency

(Be Wise, Fool's GOLD Heeds Silly HOpe)

262

Duchenne Muscular dystrophy is due to...

an X-linked frameshift mutation leading to truncated dystrophin protein leading to accelerated muscle breakdown.

263

In Duchenne Muscular dystrophy, weakness begins in...

pelvic girdle muscles and progresses superiorly. There is pseudohypertrophy of calf muscles due to fibrofatty replacement of muscle. Gower maneuver seen (pts use upper extremity to help them stand).

264

Onset of Duchenne MD is...

before 5 yrs of age and dilated cardiomyopathy is a common cause of death.

265

The dystrophin gene has...

the longest coding region of any human gene increasing its chance of spontaneous mutation.

266

Dystrophin protein helps to...

anchor muscle fibers. It connects the intracellular cytoskeleton (actin) to the transmembrane proteins alpha- and beta- dystroglycan, which are connected to the ECM.

267

Loss of dystrophin results in...

myonecrosis. Increased CPK and aldolase are seen. Western blot and muscle biopsy confirm diagnosis.

268

Becker MD is usually due to...

an X-linked point mutation in dystrophin gene (no frameshift). Onset is in adolescence; less severe than Duchenne.

269

Myotonic type 1 MD is due to a...

CTG trinucleotide repeat expansion in the DMPK gene leading to abnormal expression of myotonin protein kinse.

270

Myotonic type 1 MD presents with...

myotonia, muscle wasting, frontal balding, cataracts, testicular atrophy, and arrhythmia.

271

Fragile X syndrome is due to...

an X-linked defect affecting the methylation and expression of the FMR1 gene. Trinucleotide repeat (CGG).

272

Findings of Fragile X syndrome

-post-pubertal macroorchidism
-long face with a large jaw
-large everted ears
-autism
-mitral valve prolapse

273

Trinucleotide repeat expansion diseases (4)

1. fragile X syndrome (CGG)
2. Friedreich ataxia (GAA)
3. Huntington disease (CAG)
4. Myotonic dystrophy (CTG)

X-Girlfriend's First Aid Helped Ace My Test.

274

Down Syndrome Findings

-intellectual disability
-flat facies
-prominent epicanthal folds
-single palmar crease
-gap between 1st 2 toes
-duodenal atresia
-Hirschsprung disease
-congenital heart disease (esp. ASD)
-Brushfield spots

275

Down Syndrome is associated with...

increased risk of ALL, AML and Alzheimer.

276

Most cases of Down Syndrome are due to...

meiotic nondisjunction of homologous chormosomes leading to trisomy 21.

277

First trimester ultrasound of Down Syndrome commonly shows:

-increased nuchal translucency
-hypoplastic nasal bone
-serum PAPP-A is decreased
-free beta-hCG is increased

278

Second trimester quad screen of Down Syndrome shows:

1. decreased alpha-fetoprotein
2. increased beta-hCG
3. decreased estriol
4. increased inhibin A

279

Findings of Edwards Syndrome

1. severe intellectual disability
2. rocker-bottom feet
3. micrognathia
4. low-set ears
5. clenched hands
6. prominent occiput
7. congenital heart disease

*Death usually occurs within one year of birth.
**Trisomy 18

280

Edwards syndrome first trimester findings

decresaed PAPP-A and free beta-hCG

281

Quad screen for Edwards syndrome shows:

1. decreased alpha-fetoprotein
2. decreased beta-hCG
3. decreased estriol
4. decreased/normal inhibin

282

Findings of Patau syndrome

1. severe intellectual disability
2. rocker-bottom feet
3. microphthalmia
4. microcephaly
5. cleft lip/palate
6. holoprosencephaly
7. polydacyly
8. congenital heart disease

*Death usually occurs w/i one yr of birth.
**Trisomy 13

283

First trimester screen for Patau sydnrome shows:

-decreased beta-hCG
-decreased PAPP-A
-increased nuchal translucency

284

Robertsonian translocation is a...

nonreciprocal chromosomal translocation that commonly involves chromosome pairs 13, 14, 15, 21, and 22.

285

Robertsonia translocation occurs when...

the long arms of 2 acrocentric chromosomes fuse at the centromere and the 2 short arms are lost.

286

Unbalanced translocations can result in...

miscarriage, stillbirth, and chromosomal imablance (down syndrome, patau)

287

Cri-du-chat is a...

congenital microdeletion of the short arm of chromosome 5.

288

Findings of Cri-du-chat

microcephaly
intellectual disability
high-pitched crying (mewing)
epicanthal folds
cardiac abnormalities (VSD)

289

Williams syndrome is a...

congenital microdeletion of long arm of chr 7 (deleted region includes elastin gene).

290

Findings of Williams syndrome

-distinctive "elfin facies"
-intellectual disability
-hypercalcemia
-well-developed verbal skills
-extreme friendliness w/ strangers
-CV problems

291

22q11 deletion syndromes presentations can include...

Cleft palate, abnormal facies, thymic aplasia (leading to T-cell deficiencies, cardiac defects and hypocalcemia secondary to parathyroid aplasia

(CATCH-22)

292

22q11 deletion syndromes are due to...

aberrant devleopment of the 3rd and 4th branchial pouches.

293

DiGeorge syndrome

A 22q11 syndrome with thymic, parathyroid and cardiac defects.

294

Velocardiofacial syndrome is a...

22q11 deletion syndrome with palate, facial and cardiac defects.

295

Fat soluble vitamins are...

A, D, E and K and their absorption is dependent on gut and pancreas.

296

Toxicity of fat soluble vitamins is...

more common than for water-soluble vitamins because fat-soluble vitamins accumulate in the fat.

297

Vitamin A function

-antioxidant
-constituent of visual pigments
-needed for differentiation of epithelial cells into specialized tissue
-prevents squamous metaplasia

298

Vitamin A (retinol) is used to treat...

measles and AML (subtype M3).

299

Vitamin A deficiency causes

-night blindness (nyctalopia)
-dry, scaly skin (xerosis cutis)
-alopecia
-corneal degernation (keratomalacia)
-immune suppression

300

Vitamin A excess leads to...

arhtralgias, skin changes, cerebral edema, pseudotumor cerebri, osteoporosis, hepatic abnormalities.

(teratogen)

301

Vitamin B1 (thiamine) function

in thiamine pyrophosphate (TPP), a cofactor for:
1. pyruvate dehydrogenase
2. alpha-ketoglutarate dehydrogenase
3. transketolase
4. branched chain ketoacid dehydrogenase

302

Vitamin B1 deficiency

impaired glucose breakdown leads to ATP depletion worsened by glucose infusion; highly aerobic tissues are affected first. This is seen in malnutrition and alcoholism.

303

Diagnosis of Thiamine deficiency is made by...

increase in RBC transketolase activity following B1 adminstration.

304

Wernicke-Korsakoff syndrome

confusion, ophthalmoplegia, ataxia

(plus confabulation, personality change, memory loss)

due to damage of the medial dorsal nucleus of the thalamus, the mammillary bodies

305

Thiamine/B1 deficiency causes...

Wernicke-Korsakoff and Beriberi

306

Dry beriberi symptoms

polyneuritis, symmetrical muscle wasting

307

Wet beriberi symptoms

high-output cardiac failure, edema

308

Vitamin B2 (riboflavin) function

-components of flavins FAD and FMN, used as cofactors in redox reactions

309

Deficiency of B2/riboflavin leads to...

cheilosis and corneal vascularization

310

Function of B3/Niacin

-consitutent of NAD+ and NADP+
-used to treat dyslipidemia
-lowers levels of VLDL and raises HDL

311

Niacin is derived from...

tryptophan and its synthesis requires B2 and B6.

312

Deficiency of B3/Niacin leads to...

glossitis, pellagra (diarrhea, dementia, dermatitis)

313

Excess Niacin/B3 leads to...

facial flushing, hyperglycemia and hyperuricemia

314

B5/Pantothenate function

essential component of CoA and fatty acid synthase

315

B5/Pantothenate deficiency

-dermatitis
-enteritis
-alopecia
-adrenal insufficiency

316

B6/Pyridoxine function

-converted to pyridoxal phosphate (cofactur used in transamination, decarboxylation and glycogen phosphorylase)
-synthesis of cystathione, heme, niacin, histamine, NTs

317

Deficiency of B6/Pyroxidine leads to...

convulsions, hyperirritabiltity, peripheral neuropathy, sideroblastic anemias

318

B7/Biotin function

-cofactor fo carboxylation enzymes:
1. pyruvate carboxylase
2. acetyl-CoA carboxylase
3. propionyl-CoA carboxylase

319

B9/Folic acid function

-converted to tetrahydrofolate
-imporant for the synthesis of nitrogenous bases in DNA and RNA

320

Deficiency of B9/Folic acid leads to...

macrocytic, megaloblastic anemia
-hypersegmented PMNs
-glossitis

321

Labs of B9/Folate deficiency

-increased homocysteine
-normal methylmalonic acid

322

Deficiency of folate can be caused by several drugs:

1. phenytoin
2. sulfonamides
3. methotrexate

323

B12/cobalamin function

-cofactor for homocysteine methyltransferase and methylmalonyl-CoA mutase

324

Deficiency of B12/cobalamin leads to...

-macrocytic, megaloblastic anemia
-hypersegmented PMNs
-paresthesias
-subacute combined degeneration

325

B12/cobalamin labs

increased homocysteine
increased methlymalonic acid

326

Deficiency of B12/cobalamin is usually caused by...

insufficient intake (vegans), malabsorption (spure, D. latum), lack of IF or absence of terminal ileum.

327

Function of Vitamin C/Ascorbic acid

-antioxidant
-facilitates iron absorption by reducing it to the Fe2+ state
-hydroxylation of proline and lysine in collagen synthesis
-dopamine beta-hydroxylase

328

Deficiency of Vit C leads to...

scurvy (swollen gums, bruising, herarthrosis, anemia, poor wound healing, perifollicular and subperiosteal hemorrhages, "corkscrew hair"

329

Excess Vit C leads to...

nausea/vomiting/diarrhea/fatigue, calium oxalate nephrolithiasis
-increased risk of iron toxicity

330

Vitamin D function

-increased intestinal absorption of calcium and phosphate
-increased bone mineralization

331

Deficiency of Vitamin D leads to...

rickets in children
osteomalacia in adults
hypocalcemic tetany

332

Excess vitamin D is seen in...

sarcoidosis due to incresed activation of vitamin D by epithelioid macrophages.

333

Vitamin E function

-antioxidant (protects erythrocytes and membranes form free radical damage)

334

Vitamin E deficiency

-hemolytic anemia
-acanthocytosis
-muscle weakness
-posterior column and spinocerebellar tract demyelination

335

Vitamin K function

-cofactor for the gamma-carboxylation of glutamic acid residues on various proteins required for blood clotting
-necessary for the activation of clotting factors II, VII, IX and X

336

Vitamin K is synthesized by...

intestinal flora.

337

Vitamin K deficiency

-neonatal hemorrhage with increased PT and PTT but normal bleeding time

338

Zinc function

important for many enzymes and zinc fingers (transcription factor motif)

339

Zinc deficiency causes

-delayed wound healing
-hypogonadism
-decresed adult hair
-dysgeusia
-anosmia
-acrodermatitis enteropathica

340

In ethanol metabolism, the limiting reagent is...

NAD+.

341

Alcohol dehydrogenase operates via...

zero-order kinetics.

342

Ethanol metabolism increases the NADH/NAD+ ratio in the liver causing:

1. pyruvate -> lactate (lactic acidosis)
2. oxaloacetate -> malate (prevents gluconeogenesis and leads to fasting hypoglycemia)
3. Glyceraldehyde 3 phosphate -> glycerol-3-phosphate (combines with fatty acids to make triglycerides leading to hepatosteatosis)

343

Additionally, the increased NADH/NAD+ ratio disfavors...

TCA production of NADH leading to increased utilization of acetyl-CoA for ketogenesis leading to ketoacidosis and lipogenesis leading to hepatosteatosis.

344

Fomepizole acts to...

inhibit alcohol dehydrogenase and is an antidote for methanol or ethylene glycol poisoning.

345

Disulfiram acts to...

inhibit acetaldehyde dehydrogenase (acetaldehyde accumulates leading to hangover symptoms).

346

Kwashiorkor is...

protein malnutrition resulting in skin lesions, edema, liver malfunction (fatty change due to decreased apolipoprotein synthesis)

347

Clinical picture of Kwashiorkor is...

a small child with a swollen belly.

348

Marasmus is...

total calorie malnutrition resulting in tissue and muscle wasting, loss of subcutaneous fat and variable edema.

349

Metabolism that occurs at the mitochondria:

-fatty acid oxidation (beta-oxidation)
-acetyl-CoA production
-TCA cycle
-oxidative phosphorylation

350

Metabolism that occurs in the cytoplasm:

-glycolysis
-fatty acid synthesis
-HMP shunt
-protein synthesis (RER)
-steroid synthesis (RER)
-cholesterol synthesis

351

Metabolism that occurs in both the cytoplasm and mitochondria:

-Heme synthesis
-Urea cycle
-gluconeogenesis

352

Kinases use...

ATP to add high-energy phosphate groups onto substrates.

353

Phosphorylases act to...

add inorganic phosphate onto substrate without using ATP.

354

Phosphatase acts to...

remove phosphate group from substrate.

355

Dehydrogenase acts to...

catalyze oxidation-reduction reactions.

356

Hydroxylases act to...

add hydroxyl groups onto substrates.

357

Carboxylases act to...

transfer CO2 groups with the help of biotin.

358

Mutases act to...

relocate a functional group within a molecule.

359

Rate determining enzyme of Glycolysis

Phosphofructokinase 1 (PFK 1)

Positvely regulated by: AMP and fructose-2,6-biphosphate
Negatively regulated by: ATP and citrate

360

Rate-determining enzyme of Gluconeogenesis

Fructose-1,6-bisphosphatase

Positively regulated by: ATP and acetyl-CoA
Negatively regulated by: AMP and fructose-2,6-biphosphate

361

Rate determining enzyme of TCA cycle

Isocitrate dehydrogenase

Positively regulated by: ADP
Negatively regulated by: ATD and NADH

362

Rate determining enzyme of Glycogenesis

Glycogen synthase

Positively regulated by: Glucose-6-phosphate, inulin and cortisol
Negatively regulated by: epinephrine and glucagon

363

Rate determining enzyme of Glycogenolysis

Glycogen phosphorylase

Positively regulated by: epinephrine, glucagon, AMP
Negatively regulated by: Glucose-6-phosphate, inulin, ATP

364

Rate determining enzyme of HMP shunt

Glucose-6-phosphate dehydrogenase (G6PD)

Positively regulated by: NADP+
Negatively regulated by: NADPH

365

De novo pyrimidine synthesis rate limiting enzyme

carbamoyl phosphate syntehstase II

366

Rate determining enzyme of de novo purine synthesis

Glutamine-phosphoribosylpyrophosphate (PRPP) amidotransferase

Negatively regulated by: AMP, IMP, GMP

367

Rate determining enzyme of the urea cycle

carbamoyl phosphate synthetase I

Positively regulated by: N-acetylglutamate

368

Rate determining enzyme of fatty acid synthesis

acetyl-CoA carboxylase (ACC)

Positively regulated by: insulin and citrate
Negatively regulated by: glucagon and palmitoyl-CoA

369

Rate determining enzyme of fatty acid oxidation

carnitine acyltransferase I

Negatively regulated by: Malonyl-CoA

370

Rate-determining enzyme of Ketogenesis

HMG-CoA synthase

371

Rate determining enzyme of cholesterol synthesis

HMG-CoA reductase

Positively regulated by: insulin and thyroxine
Negatively regulated by: glucagon and cholesterol

372

Aerobic metabolism of glucose produces...

32 net ATP via the malate-aspartate shuttle (heart/liver) and 30 net ATP via the glycerol-3-phosphate shuttle (muscle)

373

Anaerobic glycolysis produces...

only 2 net ATP per glucose molecule.

374

Arsenic causes glycolysis to produce...

zero net ATP.

375

ATP carries...

phosphoryl groups.

376

NADH, NADPH, FADH2 carry...

electrons.

377

CoA and lipoamide carry...

acyl groups.

378

Biotin carries...

CO2.

379

Tetrahydrofolates carry...

1 carbon units.

380

SAM carries...

CH3 groups.

381

TPP carries...

aldehydes.

382

NAD+ is generally used in...

catabolic processes to carry reducing equivalents away as NADH.

383

NADPH is used in...

anabolic processes (steroid and fatty acid synthesis) as a supply of reducing equivalents.

384

NADPH is a produce of the...

HMP shunt.

385

NADPH is used in (4):

1. anabolic processes
2. respiratory burst
3. CYP450 system
4. glutathione reductase

386

The 1st step of glycolysis is...

phosphorylation of glucose to yield glucose-6-P.

387

The first step of glycolysis is catalyzed by either...

hexokinase or glucokinase.

388

At low glucose concentrations, hexokinase will...

sequester glucose in tissue. At high glucose concentrations, excess glucose is stored in the liver.

389

Location of hexokinsae vs. glucokinase

Hexokinase: most tissues but not liver nor beta cells of pancreas

Glucokinase: liver, beta cells of pancreas

390

Km of hexokinase vs. glucokinase

Hexokinase: lower (increased affinity)
Glucokinase: hihger (decreased affinity)

391

Vmax of hexokinase vs. glucokinase

Hexokinase: lower (decreased capacity)
Glucokinase: higher (increased capacity)

392

Induced by insulin:

Hexokinase: no
Glucokinase: yes

393

Feedback-inhibited by G-6-P:

Hexokinase: yes
Glucokinase: no

394

Gene mutation associated with maturity-onset diabetes of the young

Hexokinase: no
Glucokinase: yes

395

FBPase-2 and PFK-2 are the...

same bifunctional enzyme whose function is reversed by phosphorylation by protein kinase A.

396

In the fasting state, increased glucagon leads to...

increased cAMP leads to increased protein kinase A leads to incrases FBPase-2 and decreased PFK-2, less glycolysis and more gluconeogenesis.

397

In the fed state, increased insulin leads to...

decreased cAMP leads decreased protein kinase A which decreases FBPase-2 and increases PFK-2 leading to more glycolysis and less gluconeogenesis.

398

The pyruvate dehydrogenase complex is a...

mitochondrial enzyme complex linking glycolysis and the TCA cycle that is active in the fed state and inactive in the fasting state.

399

PDH complex catalyzes....

pyruvate + NAD+ + CoA --> acetyl-CoA + CO2 + NADH

400

The PDH complex conatins 3 enzymes that require 5 cofactors:

1. pyrophosphate (thiamine; TPP)
2. FAD (riboflavin)
3. NAD (niacin)
4. CoA (pantothenate)
5. lipoic acid

401

PDH complex is activated by...

exercise, which:
-increases NAD+/NADH ratiio
-increases ADP
-increases Ca2+

402

Arsenic inhibits....

lipoic acid leading to vomiting, rice-water stools, and garlic breath.

403

PDH complex deficiency leads to a...

buildup of pyruvate taht gets shunted to lactate (via LDH) and alanine (via ALT).

404

Findings of PDH complex deficiency

-neuro defects
-lactic acidosis
-increased serum alanine

405

Treatment for PDH complex deficiency

-increased intake of ketogenic nutrients (high fat, increased leucine and lysine)

406

4 Different Pyruvate metabolic pathways

1. alanine aminotransferase
2. pyruvate carboxylase
3. pyruvate dehydrogenase
4. lactic acid dehydrogenase

407

Alanine aminotransferase (B6) converts...

pyruvate to alanine which carries amino groups to the liver from muscle.

408

Pyruvate carboxylase (biotin) converts...

pyruvate to oxaloacetate whcih can replenish the TCA cycle or be used in gluconeogenesis.

409

Pyruvate dehydrogenase (B1, B2, B3, B5, lipoic acid) converts...

pyruvate to Acetyl-CoA which is the transition from glycolysis to the TCA cycle.

410

Lactic acid dehydrogenase (B3) converts...

pyruvate to lactate which is the end of anerobic glycolysis.

411

The TCA cycle produces...

3 NADH
1 FADH2
2 CO2
1 GTP

per acetyl-CoA (which ends up being equal to 10 ATP)

(double everything per glucose molecule)

412

TCA cycle rxns occur in...

the mitochondria.

413

The alpha-ketoglutarate dehydrogenase complex requires...

the same cofactors as the PDH complex (B1, B2, B3, B5, and lipoic acid).

414

NADH electrons from glycolysis enter the mitochondria via...

the malate-aspartate or glycerol-3-phosphate shuttle.

415

FADH2 electrons are transferred to...

complex II (at a lower energy than NADH).

416

The passage of electrons results in..

the formation of a proton gradient that, coupled to oxidative phosphorylation, drives the production of ATP.

417

1 NADH produces...

2.5 ATP.

418

1 FADH2 produces...

1.5 ATP.

419

Electron transport inhibitors...

directly inhibit electron transport, causing a decreased proton gradient and block of ATP synthesis.

420

Examples of electron transport inhibitors

Rotenone
Cyanide
Antimycin A
CO

421

ATP synthase inhibitors directly inhibit...

mitochondrial ATP synthase, causing an increased proton gradient. No ATP is produced bc electron transport stops.

422

Ex of ATP synthase inhibitor

Oligomycin

423

Uncoupling agents increase...

the permeability of the membrane, causing a decreased proton gradient and increased O2 consumption. ATP synthesis stops, but electron transport continues. Produces heat.

424

Uncoupling agent examples

1. 2,4-Dinitrophenol
2. aspirin
3. thermogenin in brown fat

425

Irreversible enzymes of gluconeogenesis

1. pyruvate carboxylase
2. phophoenolpyruvate carboxykinase
3. fructose-1,6-bisphosphatase
4. glucose-6-phosphatase

426

Pyruvate carboxylase features

-in mitochondria
-requires biotin and ATP
-activated by acetyl-CoA

427

Phosphoenolpyruvate carboxykinase features

-in cytosol
-converts oxaloacetate to phosphoenolpyruvate
-requires GTP

428

Fructose-1,6-bisphosphatase features

-in cytosol
-converts fructose-1,6-BP to fructose-6-P

429

Glucose-6-phosphatase features

-in ER
-converts glucose-6-P to glucose

430

Gluconeogenesis occurs primarily in the...

liver. It serves to maintain euglycemia during fasting.

431

Muscle cannot participate in gluconeogenesis bc...

it lacks glucose-6-phosphatase.

432

Odd-chain fatty acids yield...

1 propionyl-CoA during metabolism, which can enter the TCA cycle, undergo gluconeogenesis, and serve as a glucose source.

433

Even chain fatty acids cannot...

produce new glucose, since they yield only acetyl-CoA equivalents.

434

The HMP shunt (pentose phosphate pathway) provides...

a source of NADPH from abundantly available glucose-6-P. This pathway also yields ribose for nucleotide synthesis and glycolytic intermediates.

435

The HMP shunt has 2 distinct...

phases (oxidative and nonoxidative) both of which occur in the cytoplasm. No ATP is used or produced.

436

Sites of the HMP shunt

lactating mammary glands
liver
adrenal cortex
RBCs

437

The respiratory (or oxidative) burst involves the...

activation of the phagocyte NADPH oxidase complex (in neutrophils, monocytes) which utilizes O2 as a substrate.

438

The respiratory burst plays an important role in...

the immune response leading to rapid release of ROS.

439

Myeloperoxidase is a...

blue-green heme-containing pigment that gives sputum its color.

440

Phagocytes of pts with CGD can...

utilize H2O2 generated by invading organisms and convert it to ROS. Pts are at risk for infection by by catalase + species capable of neutralizing their own H2O2 leaving phagocytes without ROS for fighting infection.

441

Pyocyanin of P. aeruginosa functions to...

generate ROS to kill competing microbes.

442

Lactoferrin is a protein found in..

secretory fluids and neutrophils that inhibits microbial growth via iron chelation.

443

NADPH is necessary to keep...

glutathione reduced, which in turn detoxifies free radicals and peroxides.

444

Decreased NADPH in RBCs leads to...

hemolytic anemia due to poor RBC defense agaisnt oxidizing agents (fava beans, sulfonamides, primaquine, anti-TB drugs).

445

G6PDH converts...

NADP+ into NADPH.

446

Infection can also precipitate hemolysis because...

free radicals generated by inflammatory response can diffuse into RBCs and cause oxidative damage.

447

G6PDH deficiency is an...

X-linked disorder more prevalent among blacks. It gives increased malarial resistance.

448

Findings of G6PDH deficiency

-Heniz bodies
-Bite cells

449

Heinz bodies are...

oxidized Hemoglobin precipitated within RBCs

450

Bite cells result from...

the phagocytic removal of Heinz bodies by splenic macrophages.

451

Essential frucotosuria involves...

a defect in fructokinase. It is a benign condition since fructose is not trapped in cells.

452

Symptoms of Essential fructosuria

fructose appears in blood and urine

453

Fructose intolerance is a hereditary...

deficiency of aldolase B leading to accumulation of fructose-1-P causing a decrease in available pohsophate which results in inhibition of glycogenolysis and gluconeogenesis.

454

Symptoms of fructose intolerance

-hypoglycemia
-jaundice
-cirrhosis
-vomiting

455

Galactokinase deficiency is a hereditary...

deficiency of galactokinase leading to accumulation of galactose.

456

Symptoms of galactokinase deficiency

-galactose appears in blood and urine
-infantile cataracts
-may initially present as failure to track objects or to develop a social smile

457

Classic galatosemia is...

absence of galactose-1-phosphate uridyltransferase. Damage is caused by accumulation of toxic substances (like galactitol).

458

Symptoms of classic galactosemia

-FTT
-jaundice
-infantile cataracts
-hepatomegaly
-intellectual disability

459

Treatment of Classic Galactosemia

-exclude galactose and lactose from the diet

460

Classic Galactosemia can lead to...

E.coli sepsis in the neonate.

461

An alternative method of trapping glucose in a cell is to...

convert it to its alcohol counterpart, sorbitol, via aldose reductase. Some tissues then convert sorbitol to fructose using sorbitol dehydrogenase.

462

Intracellular sorbital accumulation (which occurs if there is not enough sorbitol dehydrogenase) can cause...

osmotic damage (cataracts, retinopathy and peripheral neuropathy).

463

High blood levels of glactose can also result in...

conversion to the osmotically active galactitol via aldose reductase.

464

Lactase functions on...

the brush border to digest lactose into glucose and galactose.

465

Types of lactase deficiency

Primary - age-dependent decline due to absence of lactase-persistent allele
Secondary - loss of brush border due to gastroenteritis, autoimmune disease, etc.
Congenital - rare due to a defective gene

466

The stool of those with lactase deficiency demonstrates...

decreased pH and breath shows increased hydrogen content with the lactose tolerance test.

467

Only L-form amino acids are found in...

proteins.

468

Essential Glucogenic amino acids

Mehtionine, Valine, Histidine

469

Essential Glucogenic/Ketogenic amino acids

Isoleucine, Phenylalanine, Threonine, Tryptophan

470

Essential Ketogenic amino acids

Leucine, Lysine

471

Acidic amino acids

Aspartic acid and glutamic acid

(negatively charged at body pH)

472

Basic amino acids

Arginine, Lysine, Histidine

(His has no charge at body pH)

473

Arginine and Histidine are required during...

periods of growth.

474

Arginine and Lysine are increased in...

histones, which negatively bind negatively charged DNA.

475

In the urea cycle, amino acid catabolism results in...

the formation of common metabolites (pyruvate, acetyl-CoA) which serve as metabolic fuels.

476

Excess nitrogen (NH3) generated by the urea cycle are...

converted to urea and excreted by the kidneys.

477

Hyperammonemia can be either...

acquired (liver dz) or hereditary (urea cycle enzyme deficiencies).

478

Hyperammonemia results in excess...

NH4+ which depletes alpha-ketoglutarate, leading to inhibition of the TCA cycle.

479

Treatment for hyperammonemia

limit protein in the diet; benzoate or phenylbutyrate; lactulose

480

Ammonia intoxication symptoms

-tremor (asterixis)
-slurred speech
-somnolence
-vomiting
-cerebral edema
-blurred vision

481

N-acetylglutamate deficiency is the...

lack of the required cofactor for carbamoyl phosphate synthetase I leading to hyperammonemia.

482

The presentation of N-acetylglutamate deficiency is identical to...

carbamoyl phosphate synthetse I deficiency however increased ornithine with normal urea cycle enzymes suggests hereditary N-acetylglutamate deficiency.

483

The most common urea cycle disorder is..

ornithine transcarbamylase deficiency (x-linked). It interferes with the body's ability to eliminate ammonia.

484

Ornithine transcarbamylase deficiency is often evident in...

the first few days of life but may present with late onset.

485

In ornithine transcarbamylase deficiency, excess carbamoyl phosphate is converted to...

orotic acid (as part of the pyrimidine synthesis pathway).

486

Findings of Ornithine transcarbamylase deficiency

-increased orotic acid (in blood and urine)
-decreased BUN
-symptoms of hyperammonemia
-no megalosblastic anemia

487

Phenylketonuria is due to...

decreased phenylalanine hydroxylase or decreased tetrahydrobiopterin cofactor. Tyrosine becomes essential and increased phenylalanine leads to excess phenylketones in the urine.

488

Findings of PKU (6)

1. intellectual disability
2. growth retardation
3. seizures
4. fair skin
5. eczema
6. musty body odor

489

Treatment for PKU

-decrease phenylalanine and increase tyrosine in diet

490

Maternal PKU is when...

there is a lack of proper dietary therapy during pregnancy.

491

Findings in the infant from maternal PKU (4)

1. microcephaly
2. intellectual disability
3. growth retardation
4. congenital heart defects

492

PKU is screened for...

2-3 days after birth (they are normal at birth due to maternal enzyme).

493

Phenylketones (3)

1. phenylacetate
2. pheyllactate
3. phenylpyruvate

494

The musty body order in PKU is because of ...

the disorder of ARAMATIC amino acid metabolism.

495

PKU pts must avoid...

the artificial sweetener aspartame, which contains phenylalanine.

496

Alkaptonuria is a...

congenital deficiency of homogentisate oxidase in the degradative pathway of tyrosine to fumarate.

497

Findings of alkaptonuria

dark CT, brown sclerae, urine turns black on prolonged exposure to air, debilitating arthralgia (bc homogentisic acid is toxic to cartilage)

498

3 Types of Homocystinuria

1. cystathionine synthase deficiency
2. decreased affinity of cystathionine synthase for pyridoxal phosphate
3. homocysteine methyltransferase deficiency

499

Cystathionine synthase deficiency should be treated with...

decreased methionine, increased cysteine and increased B12/folate in diet.

500

Decreased affinity of cystathionine synthase for pyridoxal phosphate should be treated with...

greatly increased B6 and cysteine in the diet.

501

Homocysteine methyltransferase (methionine synthase) deficiency should be treated with...

increased methionine in the diet.

502

Findings of Homocystinuria (8)

1. increased homocysteine in urine
2. intellectual disability
3. osteoporosis
4. tall
5. kyphosis
6. lens subluxation
7. thrombosis
8. atherosclerosis (stroke and MI)

503

Cystinuria is due to..

a hereditary defect of renal PCT and intesitnal amino acid transporter for Cysteine, Ornithine, Lysine, and Arginein (COLA).

504

Excess cystine in the urine can lead to...

precipitation of hexagonal cystine stones.

505

Diagnostic test for cystinuria is...

urinary cyanide-nitroprusside test.

506

Treatment for cystinuria

urinary alkalinization (w/ potassium citrate, acetazolamide)
and chelating agents (increase solubility of stones)

507

Maple syrup urine disease is...

blocked degradation amino acids (Isoleucine, Leucine, Valine) due to decreased alpha-ketoacid dehydrogenase (B1).

508

Maple syrup urine disease causes...

increaesed alpha-ketoacids in the blood, esp. of leucine.

509

Maple syrup urine disease leads to...

severe CNS defects, intellectual disability and death.

510

Treatment of maple syrup urine disease

restriction of leucine, isoleucine and valine in the diet and thiamine supplementation

511

Glycogen branches have...

alpha-(1,6) bodns and linkages have alpha-(1,4) bonds.

512

In skeletal muscle, glycogen....

undergoes glycogenolysis creating glucose-1-phosphate -> glucose-6-P which is rapidly metabolized during exercise.

513

In hepatocytes, glycogen is...

stored and undergoes glycogenolysis to maintain blood sugar at appropriate levels.

514

Glycogen phosphorylase acts to...

cleave glucose-1-P residues off branched glycogen until 4 remain before a branch point. Then 4-alpha-D-glucanotransferase (debranching enzyme) moves three glucose-1-Ps from the branch to the linkage. Then alpha-1,6-glucosidase (debranching enzyme) cleaves off the last glucose 1-P on the branch.

515

"limit dextran" refers to...

the one to four residues remaining on a branch after glycogen phosphorylase has already shortened it.

516

A small amount of glycogen is degraded in lysosomes by...

alpha-1,4-glucosidase (acid maltase).

517

4 Glycogen Storage Diseases

1. Von Gierke Disease
2. Pompe Disease
3. Cori Disease
4. McArdle Disease

518

Findings of Von Gierke Disease

-severe fasting hypoglycemia
-increased glycogen in liver
-increased blood lactate
-hepatomegaly

519

Deficienct enzyme in Von Gierke Disease

Glucose-6-phosphatase

520

Treatment of Von Gierke Disease

frequent oral glucose/cornstarch; avoidance of fructose and galactose

521

Pompe Disease Findings

-cardiomyopathy leading to early death

522

Pompe Disease deficienct enzymes

-lysosomal alpha-1,4-glucosidase (acid maltase)

523

Cori Disease findings

-milder form of von gierke with normal blood lactacte levels

524

Cori Disease deficient enzyme

debranching enzyme (alpha-1,6-glucosidase)

(gluconeogenesis is intact)

525

McArdle Disease findings

-increased glycogen in muscle but cannot break it down leading to painful muscle cramps, myoglobinuria with exercise, and arrhythmia from electrolyte abnormalities

526

McArdle Disease Deficient Enzyme

skeletal muscle glycogen phophorylase
(myophosphorylase)

527

Lysosomal Storage Diseases (Sphingolipidoses) (6)

1. Fabry Disease (XR)
2. Gaucher Disease (AR)
3. Niemann-Pick Disease (AR)
4. Tay-Sachs (AR)
5. Krabbe Disease (AR)
6. Metachromatic leukodystropy (AR)

528

Lysosomal Storage Diseases (Mucopolysaccharidoses) (2)

1. Hurler Syndrome (AR)
2. Hunter Syndrome (XR)

529

Fabry Disease Findings

-peripheral neuropathy of hands/feet, angiokeratomas, CV/renal disease

530

Fabry Diseaes Deficient Enzyme

alpha-galactosidase A

531

Fabry Disease Accumulated substrate

ceramide trihexoside

532

Gaucher Disease findings

-hepatosplenomegaly
-pancytopenia
-aseptic necrosis of femur
-bone crises
-Gaucher cells

533

Gaucher cells are...

lipid-laden macrophages resembling crumpled tissue paper.

534

Treatment for Gaucher Disease is...

recombinant glucocerebroside.

535

Gaucher Disease deficient enzyme

glucocerebrosidase (beta-glucosidase)

536

Gaucher diseas accumulated stubstrate

glucocerebroside

537

Niemann-Pick disease findings

-progressive neurodegeneration
-hepatosplenomegatly
-cherry red spot on macula
-foam cells (lipid-laden macrophages)

538

Niemann-Pick deficient enzyme

sphingomyelinase

539

Niemann-Pick disease accumulated substrate

sphingomyelin

540

Tay-Sachs Disease findings

-progressive neurodegeneration
-developmental delay
-cherry red spot on macula
-lysosomes with onion skin
-NO hepatosplenomegaly

541

Tay-Sachs deficient enzyme

hexosaminidase A

542

Tay-Sachs accumulated substrate

GM2 ganglioside

543

Krabbe Disease findings

-peripheral neuropathy
-developmental delay
-optic atrophy
-globoid cells

544

Krabbe disease deficient enzyme

galactocerebrosidase

545

Krabbe disease accumulated substrate

galactocerebroside psychosine

546

Metachromatic leukodystrophy findigns

-central and peripheral demyelination with ataxia
-dementia

547

Metachromatic leukodystrophy deficient enzyme

arylsulfatase A

548

Metachromatic leukodystrophy accumulated substrate

cerebroside sulfate

549

Hurler Syndrome findings

-developmental delay
-gargoylism
-airway obstruction
-corneal clouding
-hepatosplenomegaly

550

Hurler syndrome deficient enzyme

-alpha-L-iduronidase

551

Hurler syndrome accumulated substrate

heparan sulfate, dermatan sulfate

552

Hunter Syndrome findigns

-mild Hurler + aggressive behavior
-no corneal clouding

553

Hunter syndrome deficient enzyme

iduronate sulfatase

554

Hunter syndrome accumulated substrate

heparan sulfate, dermatan sulfate

555

Ashkenazi Jews have increased incidence of...

Tay-Sachs, Niemann-Pick and Gaucher.

556

Long chain fatty acid degradation requires...

carnitine-dependent transport into the mitochondrial matrix.

557

Carnitine deficiency leads to an...

inability to transport LCFAs into the mitochondria, resulting in toxic accumulation.

558

Carnitine deficiency causes...

weakness, hypotonia and hypoketotic hypoglycemia.

559

Acyl-coA dehydrogenase deficiency findings

-increased dicarboxylic acids
-decreased glucose and ketones

560

In the liver, fatty acids and amino acids are metabolized to...

acetoacetate and beta-hydroxybutyrate (to be used in the muscle and brain).

561

In prolonged starvation and diabetic ketoacidosis, there is depletion of...

oxaloacetate.

562

In alcoholism, there is excess...

NADH which shunts oxaloacetate to malate.

563

Both starvation/diabetic ketoacidosis and alcoholism cause...

a buildup of acetyl-CoA, which shunts glucose and FFA toward the production of ketone bodies.

564

Ketone bodies cause...

the breath to smell like acetone (fruity odor).

565

Urine test for ketones does not detect....

beta-hydroxybutyrate.

566

Fed state processes (3)

-glycolysis
-aerobic respiration
-insulin stimulates storage of lipids, proteins and glycogen

567

Fasting state processes (between meals) (4)

-hepatic glycogenolysis
-hepatic gluconeogenesis
-adipose release of FFA
-glucagon and adrenaline stimulate use of fuel reserves

568

Starvation (days 1-3) blood glucose levels are maintained by (4):

1. hepatic glycogenolysis (glycogen reserves depleted after day 1)
2. adipose release of FFA
3. muscle and liver shift fuel use from glucose to FFA
4. hepatic gluconeogenesis from peripheral tissue lactate and alanine, and from adipose tissue glycerol and propionyl-CoA

569

RBCs lack mitochondria so they cannot...

use ketones.

570

Starvation (after 3 days) processes

-adipose stores (ketone bodies become main fuel for brain)
*after ketone bodies are depleted, vital protein degradation accelerates leading to organ failure and death

571

The rate limiting step of cholesterol synthesis is...

catalyzed by HMG-CoA reductase (induced by insulin) which converts HMG-CoA to mevalonate.

572

2/3 of plasma cholesterol is esterified by...

lecithin-cholesterol acyltransferase (LCAT).

573

Pancreatic lipase is for degradation of...

dietary triglycerides in the small intestine.

574

Lipoprotein lipase (LPL) is for...

degradation of TG circulatin gin chylomicrons and VLDLs. Found on vascular endothelial surface.

575

Hepatic TG lipase is for degradation of...

TG remaining in IDL.

576

Hormone-sensitive lipase is for...

degradation of TG stored in adipocytes.

577

LCAT catalyzes...

esterification of cholesterol.

578

Cholesterol ester transfer protein (CETP) mediates...

transfer of cholesterol esters to other lipoprotein particles.

579

ApoE function

mediates remnant uptake

580

ApoA-1 function

activates LCAT

581

ApoC-II function

lipoprotein lipase cofactor

582

ApoB-48 function

mediates chylomicron secretion

583

ApoB-100 function

binds LDL receptor

584

Chylomicron apolipoproteins (4)

1. E
2. A-1
3. C-II
4. B-48

585

Chylomicron remnant apolipoproteins (2)

1. E
2. B-48

586

VLDL apolipoproteins (3)

1. E
2. C-II
3. B-100

587

IDL apolipoproteins (2)

1. E
2. B-100

588

LDL apolipoproteins (1)

1. B-100

589

HDL apolipoproteins (3)

1. E
2. A-I
3. C-II

590

Lipoproteins are composed of varying proportions of...

cholesterol, TGs, and phopholipids.

591

LDL and HDL carry most...

cholesterol.

592

LDL transports cholesterol from..

liver to tissues.

593

HDL transports cholesterol from...

periphery to liver.

594

Chylomicron delivers...

dietary TGs to peripheral tissue and cholesterol to the liver in the form of chylmomicron remnants.

595

Chylomicrons are secreted by...

intestinal epithelial cells.

596

VLDL delivers...

hepatic TGs to peripheral tissues. Secreted by liver.

597

IDL is formed in..

the degradation of VLDL. Delivers TGs and cholesterol to the liver.

598

LDL is formed by...

hepatic lipase modification of IDL in the peripheral tissue.

599

LDL is taken up by target cells via...

receptor-mediated endocytosis.

600

HDL acts as a repository for...

apoC and apoE (which are needed for chylomicron and VLDL metabolism).

601

HDL is secreted from both...

liver and intestine. Alcohol increases the synthesis.

602

Hyperchylomicronemia (type I) has increased blood level of...

chylomicrons, TG and cholesterol.

603

Pathophysiology of hyperchylomicronemia

lipoprotein lipase deficieny or altered apolipoproteinC-II

604

Hyperchylomicronemia causes...

pancreatitis, hepatosplenomegaly, and eruptive/pruritic xanthomas. (no increased risk of atherosclerosis)

605

Familial Hypercholesterolemia (type IIa) has increased blood levels of...

LDL and cholesterol.

606

Familial Hypercholesterolemia pathophysiology

absent or defective LDL receptors
(heterozygotes have cholesterol about equal to 300 and homozygotes have cholesterol about 700.

607

Familial hypercholesterolemia causes...

accelerated atherosclerosis (MIs before age 20), tendon xanthomas (Achilles), and corneal arcus.

608

Hypertriglyceridemia (type IV) has increased blood levels of...

VLDL and TG.

609

Hypertriglyceridemia is caused by...

hepatic overproduction of VLDL leading to pancreatitis.