Flashcards in Biochemistry - First Aid Deck (609):
DNA exists in the...
condensed, chromatin form in order to fit into the nucleus.
Negatively charged DNA loops...
twice around positively charged histone octamer to form a nucleosome "bead".
Histones are rich in...
the amino acids lysine and arginine.
H1 binds to the...
nucleosome and to linker DNA, thereby stabilizing the chromatin fiber.
In mitosis, DNA will...
condense to form chromosomes.
DNA and histone synthesis occurs during...
The only histone that is not in the DNA core is...
condensed, transcriptionally inactive, sterically inaccessibl.e.
less condensed, transcriptionally active and sterically accessible.
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.
DNA methylation at CpG islands acts to...
Histone methylation usually...
represses DNA transcription.
Histone acetylation acts to...
relax DNA coiling, allowing for transcription.
Adenine and Guanine; 2 rings
Cytosine and Thymine; 1 ring
(thymine has a methyl)
Deamination of cytosine makes...
uracil. Uracil is found in RNA; thymine in DNA.
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.
Amino acids necessary for purine synthesis
base + deoxyribose
base + deoxyribose + phoshpate
(linked by 3'5' phosphodiester bond)
Purines de novo synthesis
start with sugar + phosphate (PRPP); add base
Pyrimidine de novo synthesis
make temporary base (orotic acid); add sugar and phosphate; modify base
Ribonucleotides are synthesized...
first and are converted to deoxyribonucleotides by ribonucleotide reductase.
Carbamoyl phosphate is involved in 2 metabolic pathways:
de novo pyrimidine synthesis and the urea cycle.
Various antineoplastic and antibiotic drugs function by interfering with nucleotide synthesis:
2. Mycophenolate and Ribavirin
6. Methotrexate, trimethoprim and pyrimethamine
inhibits dihydroorotate dehydrogenase
Mycophenolate and Ribavirin inhibit...
6-MP and its prodrug Azathioprine inhibit...
de novo purine synthesis.
Methotrexate, Trimethoprim, and Pyrimethamine inhibit...
dihydrofolate reductase in humans, bacteria, and protozoa respectively.
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.
Adenosine deaminase deficiency is one of the major causes of...
Lesch-Nyhan Syndrome has...
defective purine salvage due to absent HGPRT, which converts hypoxanthine to IMP and guanine to GMP.
Lesch-Nyhan Syndrome results in...
excess uric acid production and de novo purine synthesis.
Findings of Lesch-Nyhan
Treatment for Lesch-Nyhan
Allopurinol (or Febuxostat)
Most amino acids are coded by multiple codons (degenerate/redundant) except...
methionine and tryptophan which are only encoded by 1.
In both prokaryotes and eukaryotes, DNA replication is...
semiconservative and involves both continuous and discontinous (Okazaki framgent) synthesis.
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).
The replication fork is the...
Y-shaped region along the DNA template where leading and lagging strand are synthesized.
Helicase acts to..
unwind DNA template at the replication fork.
Single-stranded binding proteins...
prevent strands from reannealing.
DNA topoisomerases create...
a single-or double-stranded break in the helix to add or remove supercoils.
an RNA primer on which DNA polymerase III can initiate replication.
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)
DNA polymerase III has...
3' to 5' exonuclease activity that "proofreads" each added nucleotide.
DNA polymerase I is only...
prokaryotic. It degrades RNA primer and replaces it with DNA.
DNA ligase catalyzes...
the formation of a phosphodiester bond within a strand of double-segmented DNA (joins Okazaki fragments).
Telomerase is an...
RNA dependent DNA polymerase taht adds DNA to 3' ends of chromosomes to avoid loss of genetic material with every duplication.
nucleotide substituion but codes for the same (synonymous) amino acid; often base change in the 3rd position of the codon (tRNA wobble)
nucleotide substitution resulting in changed amino acid (called conservative if the new amino acid is similar in chemical structure)
(ex. sickle cell disease)
nucleotide substitution resulting in an early stop codon
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
Nucleotide excision repair
specific endonucleases release the oligonucleotide-containing damaged bases; DNA polymerase and ligase fill and reseal the gap
Nucleotide excision repair repairs...
bulky helix-distorting lesions.
Nucleotide excision repair is defective in...
xeroderma pigmentosum, which prevents repair of pyrimidine dimers because of UV light exposure.
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
Base excision repair is important in the repair of...
newly synthesized strand is recognized, mismatched nucleotides are removed and the gap is filled and resealed
Mismatch repair is defective in...
HNPCC (hereditary nonpolyposis colorectal cancer).
Nonhomologous end joining brings together...
2 ends of DNA fragments to repair double-stranded breaks.
Nonhomologous end joining is mutated in...
DNA and RNA are both synthesized...
5' to 3'. The 5' end of the incoming nucleotide bears the triphosphate (energy source for the bond).
Protein synthesis is...
N-terminus to C-terminus.
mRNA is read...
5' to 3'.
The target of the 3' hydroxyl attack is...
the triphosphate bond.
Drugs blocking DNA replication often have...
modified 3' OH, preventing addition of the next nucleotide (chain termination).
mRNA start codon
AUG. In eukaryotes, AUG codes for methionine. In prokaryotes, it codes for f-met.
mRNA stop codons
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).
Promoter mutation commonly results in...
dramatic decrease in the level of gene transcription.
Enhancer is a...
stretch of DNA that alters gene expression by binding transcription factors.
Silencer is the...
site where negative regulators bind.
RNA polymerase I makes..
rRNA (most numerous RNA).
RNA polymerase II makes...
mRNA (largest RNA).
RNA polymerase III makes...
tRNA (smallest RNA).
RNA polymerases do not have...
proofreading function but they can initiate chains.
Prokaryotes only have one...
RNA polymerase that makes all 3 kinds of RNA.
alpha-amanitin found in...
Amanita phalloides (death cap mushrooms) inhibits RNA polymerase II and causes severe hepatotoxicity.
The initial RNA transcript is called...
heterogenous nuclear RNA (hnRNA) and it is then modified to become mRNA.
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)
mRNA is transported...
out of the nuclues into the cytosol, where it is translated.
mRNA quality control occurs at...
cytoplasmic P-bodies, which contain exonucleases, decapping enzymes, and microRNAs.
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.
Antibodies to the spliceosomal snRLNPs (anti-Smith antibodies) are highly specific for...
Anti-U1 RNp antibodies are highly associated with...
mixed connective tissue disease.
the actual genetic info coding for protein. Introns are intervening noncoding segments of DNA.
Different exons are frequently...
combined by alternative splicing to produce a larger number of unique proteins.
Abnormal splicing variants are implicated in...
oncogenesis and beta-thalassemia, etc.
-anticodon end is opposite 3' aminoacyl end
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.
T-arm of tRNA
contains the thymine, pseudouridine, cytosine sequence necessary for tRNA-ribosome binding
D-arm of tRNA
contains dihydrouracil residues necessary for tRNA recognition by the correct aminoacyl-tRNA synthetase
Acceptor stem of tRNA
the 3' CCA is the amino acid acceptor site
Aminoacyl-tRNA synthetase (1/amino acid; matchmaker; uses ATP) scrutinizes...
amino acid before and after it binds tRNA. If incorrect, the bond is hydrolyzed.
The amino acid-tRNA bond has nergy for..
formation of a peptide bond.
A mischarged tRNA reads...
the usual codon but inserts the wrong amino acid.
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.
3 steps of protein synthesis
Protein synthesis is iniated by...
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.
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
stop codon is reconized by release factor and completed polypeptide is released from the ribosome
the removal of N- or C- terminal propeptides from the zymogen to generat a mature protein
Covalent alterations include...
phophorylation, glycosylation, hydroxylation, methylation, acetylation and ubiquitination
intracellular protein involved in facilitating and/or maintaining protein folding
Mitosis (the shortest phase of the cell cycle) incudes...
prophase, metaphase, anaphase and telophase.
G1 and G0 are of...
consititutive and inactive.
regulatory proteins that control the cell cycle events; phase specific; activate CDKs.
Cyclin-CDK complexes must be...
activated and inactivated for cell cycle to progress.
Tumor suppressors p53 and hypophosphorylated Rb normally...
inhibit G1 to S progression; mutations in these genes result in unrestrained cell division (Li-Fraumeni syndrome).
Permanent cell types remain in...
G0, they regenerate from stem cells.
Examples of permanent cells
skeletal and cardiac muscle
Stable (quiesent) cells enter...
G1 from G0 when stimulated.
Examples of stable cells include...
hepatocytes and lymphocytes.
Labile cells never...
goto G0; they divide rapidly with a short G1. These are the cells most affected by chemo.
Examples of labile cells
Rough endoplasmic reticulum is the site of..
syntehsis of secretory proteins and of N-linked oligosaccharide addition to proteins.
Nissle bodies (RER in neurons) synthesize...
peptide NTs for secretion.
Free ribosomes are the site of synthesis of...
cytosolic and organellar proteins.
Cells rich in RER are...
mucus-secreting goblet cells and antibody-secreting plasma cells.
Smooth endoplasmic reticulum is the site of...
steroid syntehsis and detoxification of drugs and poisons; lacks surface ribosomes.
Cells rich in SER include...
liver hepatocyte sand steroid hormone-producing cells of the adrenal cortex.
The golgi is the...
distribution center for proteins and lipids from the ER to the vesicles and plasma membrane.
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
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.
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.
I-cell disease results in...
coarse facial features, clouded corneas, restricted joint movement, and high plasma levels of lysosomal enzymes. Often fatal in childhood.
Signal recognition particle (SRP) is an...
abundant, cytosolic ribonucleoprotein that traffics proteins from the ribosome to the RER.
Absent/dysfunctional SRP leads to...
protein accumulation in the cytosol.
Vesicular trafficking proteins (3)
COPI traffics from...
the Golgi to the Golgi (retrograde) and from the Golgi to the ER.
COPII traffics from...
the Golgi to the Golgi (anterograde) and from the ER to the Golgi.
Clatrhin traffics from...
the trans-Golgi to the lysosomes; and from plasma membrane to endosomes
Peroxisome is a...
membrane-enclosed organelle involved in catabolism of very long chain fatty acids, branched chain fatty acids and amino acids.
Proteasome is a...
barrel-shaped protein complex that degrades damaged or ubiquitin-tagged proteins.
cyclindrical structures composed of a helical array of polymerized heterodimers of alpha and beta tubulin. Each dimer has 2 GTP bound.
Microtubules are incorporated into..
flagella, cilia, and mitotic spindles and centrioles. Also involved in slow axoplasmic transport in neurons.
slowly and collapse quickly.
Molecular motor proteins transport...
cellular cargo toward opposite ends of microtubule tracks.
retrograde to microtubule (+ to -)
anterograde to microtuble (- to +)
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)
9 + 2 arrangement of microtubules
Axonemal dynein is...
ATPase that links peripheral 9 doublets and casues bending of cilium by differential sliding of doublets.
Kartagener Syndrome (primary ciliary dyskinesia)
immotile cilia due to a dynein arm defect.
Kartagener results in...
male/female infertility due to immotile sperm and dysfunctional fallopian tube cilia. Increases the risk of ectopic pregnancy.
Kartagener can cause...
bronchiectasis, recurrent sinusitis and situs inversus.
Actin and myosin are used in:
1. muscle contraction
4. adherens junction
long, structural polymers.
dimeric, ATP-driven motor proteins that move along actins.
Intermediate filaments give structure and include....
glial fibrillary acid proteins (GFAPs)
The plasma membrane is an asymmetric lipid bilayer that contains...
cholesterol, phospholipids, sphingolipids, glycolipids, and proteins.
Vimentin stain is for...
Desmin stain is for...
Cytokeratin stain is for...
GFAP is for...
Neurofilaments stain for...
The Na+/K+ ATPase is locatd in the...
plasma membrane with ATP site on the cytosolic side.
For each ATP consumed in the Na/K ATPase...
3 Na+ go out and 2 K+ come in.
Ouabain acts to...
inhibit the Na/K ATPase by binding to the K+ site.
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.
The most abundant protein in the human body is...
collagen. It is extensively modified by posttranslational modification. It organizes and strengthens ECM.
Type I collagen
-most common (90%)
-late wound repair
There is decreased production of Type I collagen in...
osteogenesis imperfecta type I.
Type II collagen
Type III Cartilage
Type III collagen deficiency is...
uncommon. An example is the vascular type of Ehlers-Danos.
Type IV collagen
Type IV collagen is defective in...
Alport sydnrome and is targeted by autoantibodies in goodpasture syndrome.
Collagen Synthesis 4 Steps
1. Synthesis (RER)
2. Hydroxylation (RER)
3. Glycosylation (RER)
5. Proteolytic Processing (outside fibroblast)
6. Cross-linking (outside fibroblast)
Syntehsis of collagen
translation of collagen alpha chains (preprocollagen) - usually Gly-X-Y (proline or lysine)
Hydroxylation of collagen
hydroxylation of specific proline and lysine residues (requires Vitamin C; deficiency leads to scurvy)
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)
Problems forming the collagen triple helix leads to...
Exocytosis of collagen
exocytosis of procollagen into extracellular space
Proteolytic processing of collagen
cleavage of disulfide rich terminal regions of procollagen, transforming it into insoluble tropocollagen
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.
Problems with collagen cross-linking lead to...
Osteogenesis imperfecta is...
a genetic bone disorder (brittle) caused by many defects. The most common one being decreased production of normal collagen (AD).
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)
Ehlers-Danos is due to...
faulty collagen synthesis, causing hyperextensible skin, tendency to bleed and hypermobile joints.
Ehlers-Danos may be associated with...
joint dislocation, berry/aortic aneurysms and organ rupture.
Hypermobility type of Ehlers-Danos
-mutation in type V collagen
-joint and skin symptoms
Vascular type of Ehlers-Danos
-deficienct type III collagen
-vascular and oran rupture
Menkes disease is a...
CT disease caused by impaired copper absorption and transport.
Menkes disease leads to...
decreased activity of lysyl oxidase (copper is a necessary cofactor)
Menkes disease results in...
brittle, kinky hair, growth retardation and hypotonia.
Elastin is a...
stretchy protein within skin, lungs, large arteries, elastic ligaments, vocal cords and ligamenta flava.
Elastin is rich in...
proline and glycine, nonhydroxylated forms.
Components of elastin include...
tropoelastin with fibrillin scaffolding.
Cross-linking of elastin takes place...
extracelullarly and gives elastin its elastic properties.
Elastin is broken down by...
elastase which is normally inhibited by alpha1-antitrypsin.
Marfan syndrome is caused by...
a defect in fibrillin, a glycoprotein that forms a sheath aroun elastin.
Emphysema can be caused by...
alpha1-antitrypsin deficiency, resulting in excess elastase activity.
Wrinkles of aging are due to...
decreased collagen and elastin production.
Polymerase Chain Rxn (PCR) is a lab procedure used to...
amplify a desired fragment of DNA.
3 steps of PCR
DNA is denatured by heating to generate 2 separate strands.
during cooling, excess premade DNA primers anneal to a specific sequence on each strand to be amplified
heat-stable DNA polyemerase replicates the DNA sequence following each primer
Agarose gel electrophoresis is used for...
size separation of PCR products (smaller molecules travel further) which can then be compared to a DNA ladder.
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.
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.
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.
The confirmatory test for HIV after positive ELISA screening is...
Southwestern blot identifies...
DNA-binding proteins (transription factors, etc) using labeled oligonucleotide probes.
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.
Microarrays are used to...
profile gene expression levels of thousands of genes simultaneously to study certain diseases and treatments.
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.
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.
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.
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.
Both the sensitivity and specificity of ELISA approach...
100% but false-positives and false-negatives do occur.
Fluorescence in situ hybridization (FISH) uses a...
fluorescent DNA or RNA probe that binds to specific gene site of interest on chromosomes.
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).
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
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
The cre-lox system can inducibly...
manipulate genes at specific developmental points (ex. to study a gene whose deletion causes embryonic death).
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.
Karyotyping is a process by which ...
metaphase chromosomes are stained, ordered and numbered according to morphology, size, arm-length ratio and banding pattern.
Karyotyping can be performed on a sample of...
blood, bone marrow, amniotic fluid, or placental tissue.
Karyotyping is used to diagnose...
chromosomal imbalances (ex. autosomal trisomies, sex chromosome disorders).
both alleles contribute to the phenotype of the heterozygote
(ex. blood groups; alpha-antityrpsin deficiency)
phenotype varies among individuals with the same genotype
(ex. 2 pts have NF1 may have varying disease severity)
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)
one gene contributes to multiple phenotypic effects
(ex. untreated PKU manifests with light skin, intellectual disability and musty body odor)
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
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)
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
presence of genetically distinct cell lines in the same individual; arises from mitotic errors after fertilization
mutation propagates through multiple tissues or organs
mutation only in egg or sperm cells
mutations at different loci can produce a similar phenotype
different mutations in the same locuse produce the same phenotype
presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrial inherited disease
Uniparental disomy is when...
an offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent.
Heterodisomy (heterzygous) indicates a...
meiosis I error.
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.
Consider uniparental disomy in an individual manifesting...
a recessive disorder when only one parent is a carrier.
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.
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
The frequency of an X-linked recessive disease in males is...
q and in females it is q^2.
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
Maternal imprinting: gene from mom is normally silent and paternal gene is deletered
Prader-Willi Syndrome leads to...
hyperphagia, obesity, intellectual disability, hypogonadism, and hypotonia.
Paternal imprinting: gene from dad is normally silent and maternal gene is deleted.
Angelman Syndrome results in...
inappropriate laughter, seizures, ataxia and intellectual disability.
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
Mitochondrial inheritance is transmitted...
only through the mother. All offspring of affected mothers may show signs fo disease.
Mitochondrial myopathies are rare disorders that present with...
myopathy, lactic acidosis and CNS disease. Secondary to oxidative phosphorylation; "ragged red fibers" on muscle biopsy.
Cystic Fibrosis Genetics
autosomal recessive defect in CFTR gene on chr 7; commonly a deletion of Phe508
an ATP-gated Cl- channel that secretes Cl- in the lungs and GI tract and reabsorbs Cl- in the sweat glands
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.
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.
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.
Treatment for Cystic Fibrosis
-N-acetylcysteine to loosen mucus plugs (cleaves disulfide bonds within mucus glycoproteins)
-dornase alfa (DNAse to clear leukocytic debris)
X-linked recessive disorders
-Duchenne (and Becker) muscular dystrophy
-Hemophilia A and B
-Ornithine transcarbamylase deficiency
(Be Wise, Fool's GOLD Heeds Silly HOpe)
Duchenne Muscular dystrophy is due to...
an X-linked frameshift mutation leading to truncated dystrophin protein leading to accelerated muscle breakdown.
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).
Onset of Duchenne MD is...
before 5 yrs of age and dilated cardiomyopathy is a common cause of death.
The dystrophin gene has...
the longest coding region of any human gene increasing its chance of spontaneous mutation.
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.
Loss of dystrophin results in...
myonecrosis. Increased CPK and aldolase are seen. Western blot and muscle biopsy confirm diagnosis.
Becker MD is usually due to...
an X-linked point mutation in dystrophin gene (no frameshift). Onset is in adolescence; less severe than Duchenne.
Myotonic type 1 MD is due to a...
CTG trinucleotide repeat expansion in the DMPK gene leading to abnormal expression of myotonin protein kinse.
Myotonic type 1 MD presents with...
myotonia, muscle wasting, frontal balding, cataracts, testicular atrophy, and arrhythmia.
Fragile X syndrome is due to...
an X-linked defect affecting the methylation and expression of the FMR1 gene. Trinucleotide repeat (CGG).
Findings of Fragile X syndrome
-long face with a large jaw
-large everted ears
-mitral valve prolapse
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.
Down Syndrome Findings
-prominent epicanthal folds
-single palmar crease
-gap between 1st 2 toes
-congenital heart disease (esp. ASD)
Down Syndrome is associated with...
increased risk of ALL, AML and Alzheimer.
Most cases of Down Syndrome are due to...
meiotic nondisjunction of homologous chormosomes leading to trisomy 21.
First trimester ultrasound of Down Syndrome commonly shows:
-increased nuchal translucency
-hypoplastic nasal bone
-serum PAPP-A is decreased
-free beta-hCG is increased
Second trimester quad screen of Down Syndrome shows:
1. decreased alpha-fetoprotein
2. increased beta-hCG
3. decreased estriol
4. increased inhibin A
Findings of Edwards Syndrome
1. severe intellectual disability
2. rocker-bottom feet
4. low-set ears
5. clenched hands
6. prominent occiput
7. congenital heart disease
*Death usually occurs within one year of birth.
Edwards syndrome first trimester findings
decresaed PAPP-A and free beta-hCG
Quad screen for Edwards syndrome shows:
1. decreased alpha-fetoprotein
2. decreased beta-hCG
3. decreased estriol
4. decreased/normal inhibin
Findings of Patau syndrome
1. severe intellectual disability
2. rocker-bottom feet
5. cleft lip/palate
8. congenital heart disease
*Death usually occurs w/i one yr of birth.
First trimester screen for Patau sydnrome shows:
-increased nuchal translucency
Robertsonian translocation is a...
nonreciprocal chromosomal translocation that commonly involves chromosome pairs 13, 14, 15, 21, and 22.
Robertsonia translocation occurs when...
the long arms of 2 acrocentric chromosomes fuse at the centromere and the 2 short arms are lost.
Unbalanced translocations can result in...
miscarriage, stillbirth, and chromosomal imablance (down syndrome, patau)
Cri-du-chat is a...
congenital microdeletion of the short arm of chromosome 5.
Findings of Cri-du-chat
high-pitched crying (mewing)
cardiac abnormalities (VSD)
Williams syndrome is a...
congenital microdeletion of long arm of chr 7 (deleted region includes elastin gene).
Findings of Williams syndrome
-distinctive "elfin facies"
-well-developed verbal skills
-extreme friendliness w/ strangers
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
22q11 deletion syndromes are due to...
aberrant devleopment of the 3rd and 4th branchial pouches.
A 22q11 syndrome with thymic, parathyroid and cardiac defects.
Velocardiofacial syndrome is a...
22q11 deletion syndrome with palate, facial and cardiac defects.
Fat soluble vitamins are...
A, D, E and K and their absorption is dependent on gut and pancreas.
Toxicity of fat soluble vitamins is...
more common than for water-soluble vitamins because fat-soluble vitamins accumulate in the fat.
Vitamin A function
-constituent of visual pigments
-needed for differentiation of epithelial cells into specialized tissue
-prevents squamous metaplasia
Vitamin A (retinol) is used to treat...
measles and AML (subtype M3).
Vitamin A deficiency causes
-night blindness (nyctalopia)
-dry, scaly skin (xerosis cutis)
-corneal degernation (keratomalacia)
Vitamin A excess leads to...
arhtralgias, skin changes, cerebral edema, pseudotumor cerebri, osteoporosis, hepatic abnormalities.
Vitamin B1 (thiamine) function
in thiamine pyrophosphate (TPP), a cofactor for:
1. pyruvate dehydrogenase
2. alpha-ketoglutarate dehydrogenase
4. branched chain ketoacid dehydrogenase
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.
Diagnosis of Thiamine deficiency is made by...
increase in RBC transketolase activity following B1 adminstration.
confusion, ophthalmoplegia, ataxia
(plus confabulation, personality change, memory loss)
due to damage of the medial dorsal nucleus of the thalamus, the mammillary bodies
Thiamine/B1 deficiency causes...
Wernicke-Korsakoff and Beriberi
Dry beriberi symptoms
polyneuritis, symmetrical muscle wasting
Wet beriberi symptoms
high-output cardiac failure, edema
Vitamin B2 (riboflavin) function
-components of flavins FAD and FMN, used as cofactors in redox reactions
Deficiency of B2/riboflavin leads to...
cheilosis and corneal vascularization
Function of B3/Niacin
-consitutent of NAD+ and NADP+
-used to treat dyslipidemia
-lowers levels of VLDL and raises HDL
Niacin is derived from...
tryptophan and its synthesis requires B2 and B6.
Deficiency of B3/Niacin leads to...
glossitis, pellagra (diarrhea, dementia, dermatitis)
Excess Niacin/B3 leads to...
facial flushing, hyperglycemia and hyperuricemia
essential component of CoA and fatty acid synthase
-converted to pyridoxal phosphate (cofactur used in transamination, decarboxylation and glycogen phosphorylase)
-synthesis of cystathione, heme, niacin, histamine, NTs
Deficiency of B6/Pyroxidine leads to...
convulsions, hyperirritabiltity, peripheral neuropathy, sideroblastic anemias
-cofactor fo carboxylation enzymes:
1. pyruvate carboxylase
2. acetyl-CoA carboxylase
3. propionyl-CoA carboxylase
B9/Folic acid function
-converted to tetrahydrofolate
-imporant for the synthesis of nitrogenous bases in DNA and RNA
Deficiency of B9/Folic acid leads to...
macrocytic, megaloblastic anemia
Labs of B9/Folate deficiency
-normal methylmalonic acid
Deficiency of folate can be caused by several drugs:
-cofactor for homocysteine methyltransferase and methylmalonyl-CoA mutase
Deficiency of B12/cobalamin leads to...
-macrocytic, megaloblastic anemia
-subacute combined degeneration
increased methlymalonic acid
Deficiency of B12/cobalamin is usually caused by...
insufficient intake (vegans), malabsorption (spure, D. latum), lack of IF or absence of terminal ileum.
Function of Vitamin C/Ascorbic acid
-facilitates iron absorption by reducing it to the Fe2+ state
-hydroxylation of proline and lysine in collagen synthesis
Deficiency of Vit C leads to...
scurvy (swollen gums, bruising, herarthrosis, anemia, poor wound healing, perifollicular and subperiosteal hemorrhages, "corkscrew hair"
Excess Vit C leads to...
nausea/vomiting/diarrhea/fatigue, calium oxalate nephrolithiasis
-increased risk of iron toxicity
Vitamin D function
-increased intestinal absorption of calcium and phosphate
-increased bone mineralization
Deficiency of Vitamin D leads to...
rickets in children
osteomalacia in adults
Excess vitamin D is seen in...
sarcoidosis due to incresed activation of vitamin D by epithelioid macrophages.
Vitamin E function
-antioxidant (protects erythrocytes and membranes form free radical damage)
Vitamin E deficiency
-posterior column and spinocerebellar tract demyelination
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
Vitamin K is synthesized by...
Vitamin K deficiency
-neonatal hemorrhage with increased PT and PTT but normal bleeding time
important for many enzymes and zinc fingers (transcription factor motif)
Zinc deficiency causes
-delayed wound healing
-decresed adult hair
In ethanol metabolism, the limiting reagent is...
Alcohol dehydrogenase operates via...
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)
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.
Fomepizole acts to...
inhibit alcohol dehydrogenase and is an antidote for methanol or ethylene glycol poisoning.
Disulfiram acts to...
inhibit acetaldehyde dehydrogenase (acetaldehyde accumulates leading to hangover symptoms).
protein malnutrition resulting in skin lesions, edema, liver malfunction (fatty change due to decreased apolipoprotein synthesis)
Clinical picture of Kwashiorkor is...
a small child with a swollen belly.
total calorie malnutrition resulting in tissue and muscle wasting, loss of subcutaneous fat and variable edema.
Metabolism that occurs at the mitochondria:
-fatty acid oxidation (beta-oxidation)
Metabolism that occurs in the cytoplasm:
-fatty acid synthesis
-protein synthesis (RER)
-steroid synthesis (RER)
Metabolism that occurs in both the cytoplasm and mitochondria:
ATP to add high-energy phosphate groups onto substrates.
Phosphorylases act to...
add inorganic phosphate onto substrate without using ATP.
Phosphatase acts to...
remove phosphate group from substrate.
Dehydrogenase acts to...
catalyze oxidation-reduction reactions.
Hydroxylases act to...
add hydroxyl groups onto substrates.
Carboxylases act to...
transfer CO2 groups with the help of biotin.
Mutases act to...
relocate a functional group within a molecule.
Rate determining enzyme of Glycolysis
Phosphofructokinase 1 (PFK 1)
Positvely regulated by: AMP and fructose-2,6-biphosphate
Negatively regulated by: ATP and citrate
Rate-determining enzyme of Gluconeogenesis
Positively regulated by: ATP and acetyl-CoA
Negatively regulated by: AMP and fructose-2,6-biphosphate
Rate determining enzyme of TCA cycle
Positively regulated by: ADP
Negatively regulated by: ATD and NADH
Rate determining enzyme of Glycogenesis
Positively regulated by: Glucose-6-phosphate, inulin and cortisol
Negatively regulated by: epinephrine and glucagon
Rate determining enzyme of Glycogenolysis
Positively regulated by: epinephrine, glucagon, AMP
Negatively regulated by: Glucose-6-phosphate, inulin, ATP
Rate determining enzyme of HMP shunt
Glucose-6-phosphate dehydrogenase (G6PD)
Positively regulated by: NADP+
Negatively regulated by: NADPH
De novo pyrimidine synthesis rate limiting enzyme
carbamoyl phosphate syntehstase II
Rate determining enzyme of de novo purine synthesis
Glutamine-phosphoribosylpyrophosphate (PRPP) amidotransferase
Negatively regulated by: AMP, IMP, GMP
Rate determining enzyme of the urea cycle
carbamoyl phosphate synthetase I
Positively regulated by: N-acetylglutamate
Rate determining enzyme of fatty acid synthesis
acetyl-CoA carboxylase (ACC)
Positively regulated by: insulin and citrate
Negatively regulated by: glucagon and palmitoyl-CoA
Rate determining enzyme of fatty acid oxidation
carnitine acyltransferase I
Negatively regulated by: Malonyl-CoA
Rate-determining enzyme of Ketogenesis
Rate determining enzyme of cholesterol synthesis
Positively regulated by: insulin and thyroxine
Negatively regulated by: glucagon and cholesterol
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)
Anaerobic glycolysis produces...
only 2 net ATP per glucose molecule.
Arsenic causes glycolysis to produce...
zero net ATP.
NADH, NADPH, FADH2 carry...
CoA and lipoamide carry...
1 carbon units.
NAD+ is generally used in...
catabolic processes to carry reducing equivalents away as NADH.
NADPH is used in...
anabolic processes (steroid and fatty acid synthesis) as a supply of reducing equivalents.
NADPH is a produce of the...
NADPH is used in (4):
1. anabolic processes
2. respiratory burst
3. CYP450 system
4. glutathione reductase
The 1st step of glycolysis is...
phosphorylation of glucose to yield glucose-6-P.
The first step of glycolysis is catalyzed by either...
hexokinase or glucokinase.
At low glucose concentrations, hexokinase will...
sequester glucose in tissue. At high glucose concentrations, excess glucose is stored in the liver.
Location of hexokinsae vs. glucokinase
Hexokinase: most tissues but not liver nor beta cells of pancreas
Glucokinase: liver, beta cells of pancreas
Km of hexokinase vs. glucokinase
Hexokinase: lower (increased affinity)
Glucokinase: hihger (decreased affinity)
Vmax of hexokinase vs. glucokinase
Hexokinase: lower (decreased capacity)
Glucokinase: higher (increased capacity)
Induced by insulin:
Feedback-inhibited by G-6-P:
Gene mutation associated with maturity-onset diabetes of the young
FBPase-2 and PFK-2 are the...
same bifunctional enzyme whose function is reversed by phosphorylation by protein kinase A.
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.
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.
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.
PDH complex catalyzes....
pyruvate + NAD+ + CoA --> acetyl-CoA + CO2 + NADH
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
PDH complex is activated by...
-increases NAD+/NADH ratiio
lipoic acid leading to vomiting, rice-water stools, and garlic breath.
PDH complex deficiency leads to a...
buildup of pyruvate taht gets shunted to lactate (via LDH) and alanine (via ALT).
Findings of PDH complex deficiency
-increased serum alanine
Treatment for PDH complex deficiency
-increased intake of ketogenic nutrients (high fat, increased leucine and lysine)
4 Different Pyruvate metabolic pathways
1. alanine aminotransferase
2. pyruvate carboxylase
3. pyruvate dehydrogenase
4. lactic acid dehydrogenase
Alanine aminotransferase (B6) converts...
pyruvate to alanine which carries amino groups to the liver from muscle.
Pyruvate carboxylase (biotin) converts...
pyruvate to oxaloacetate whcih can replenish the TCA cycle or be used in gluconeogenesis.
Pyruvate dehydrogenase (B1, B2, B3, B5, lipoic acid) converts...
pyruvate to Acetyl-CoA which is the transition from glycolysis to the TCA cycle.
Lactic acid dehydrogenase (B3) converts...
pyruvate to lactate which is the end of anerobic glycolysis.
The TCA cycle produces...
per acetyl-CoA (which ends up being equal to 10 ATP)
(double everything per glucose molecule)
TCA cycle rxns occur in...
The alpha-ketoglutarate dehydrogenase complex requires...
the same cofactors as the PDH complex (B1, B2, B3, B5, and lipoic acid).
NADH electrons from glycolysis enter the mitochondria via...
the malate-aspartate or glycerol-3-phosphate shuttle.
FADH2 electrons are transferred to...
complex II (at a lower energy than NADH).
The passage of electrons results in..
the formation of a proton gradient that, coupled to oxidative phosphorylation, drives the production of ATP.
1 NADH produces...
1 FADH2 produces...
Electron transport inhibitors...
directly inhibit electron transport, causing a decreased proton gradient and block of ATP synthesis.
Examples of electron transport inhibitors
ATP synthase inhibitors directly inhibit...
mitochondrial ATP synthase, causing an increased proton gradient. No ATP is produced bc electron transport stops.
Ex of ATP synthase inhibitor
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.
Uncoupling agent examples
3. thermogenin in brown fat
Irreversible enzymes of gluconeogenesis
1. pyruvate carboxylase
2. phophoenolpyruvate carboxykinase
Pyruvate carboxylase features
-requires biotin and ATP
-activated by acetyl-CoA
Phosphoenolpyruvate carboxykinase features
-converts oxaloacetate to phosphoenolpyruvate
-converts fructose-1,6-BP to fructose-6-P
-converts glucose-6-P to glucose
Gluconeogenesis occurs primarily in the...
liver. It serves to maintain euglycemia during fasting.
Muscle cannot participate in gluconeogenesis bc...
it lacks glucose-6-phosphatase.
Odd-chain fatty acids yield...
1 propionyl-CoA during metabolism, which can enter the TCA cycle, undergo gluconeogenesis, and serve as a glucose source.
Even chain fatty acids cannot...
produce new glucose, since they yield only acetyl-CoA equivalents.
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.
The HMP shunt has 2 distinct...
phases (oxidative and nonoxidative) both of which occur in the cytoplasm. No ATP is used or produced.
Sites of the HMP shunt
lactating mammary glands
The respiratory (or oxidative) burst involves the...
activation of the phagocyte NADPH oxidase complex (in neutrophils, monocytes) which utilizes O2 as a substrate.
The respiratory burst plays an important role in...
the immune response leading to rapid release of ROS.
Myeloperoxidase is a...
blue-green heme-containing pigment that gives sputum its color.
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.
Pyocyanin of P. aeruginosa functions to...
generate ROS to kill competing microbes.
Lactoferrin is a protein found in..
secretory fluids and neutrophils that inhibits microbial growth via iron chelation.
NADPH is necessary to keep...
glutathione reduced, which in turn detoxifies free radicals and peroxides.
Decreased NADPH in RBCs leads to...
hemolytic anemia due to poor RBC defense agaisnt oxidizing agents (fava beans, sulfonamides, primaquine, anti-TB drugs).
NADP+ into NADPH.
Infection can also precipitate hemolysis because...
free radicals generated by inflammatory response can diffuse into RBCs and cause oxidative damage.
G6PDH deficiency is an...
X-linked disorder more prevalent among blacks. It gives increased malarial resistance.
Findings of G6PDH deficiency
Heinz bodies are...
oxidized Hemoglobin precipitated within RBCs
Bite cells result from...
the phagocytic removal of Heinz bodies by splenic macrophages.
Essential frucotosuria involves...
a defect in fructokinase. It is a benign condition since fructose is not trapped in cells.
Symptoms of Essential fructosuria
fructose appears in blood and urine
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.
Symptoms of fructose intolerance
Galactokinase deficiency is a hereditary...
deficiency of galactokinase leading to accumulation of galactose.
Symptoms of galactokinase deficiency
-galactose appears in blood and urine
-may initially present as failure to track objects or to develop a social smile
Classic galatosemia is...
absence of galactose-1-phosphate uridyltransferase. Damage is caused by accumulation of toxic substances (like galactitol).
Symptoms of classic galactosemia
Treatment of Classic Galactosemia
-exclude galactose and lactose from the diet
Classic Galactosemia can lead to...
E.coli sepsis in the neonate.
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.
Intracellular sorbital accumulation (which occurs if there is not enough sorbitol dehydrogenase) can cause...
osmotic damage (cataracts, retinopathy and peripheral neuropathy).
High blood levels of glactose can also result in...
conversion to the osmotically active galactitol via aldose reductase.
Lactase functions on...
the brush border to digest lactose into glucose and galactose.
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
The stool of those with lactase deficiency demonstrates...
decreased pH and breath shows increased hydrogen content with the lactose tolerance test.
Only L-form amino acids are found in...
Essential Glucogenic amino acids
Mehtionine, Valine, Histidine
Essential Glucogenic/Ketogenic amino acids
Isoleucine, Phenylalanine, Threonine, Tryptophan
Essential Ketogenic amino acids
Acidic amino acids
Aspartic acid and glutamic acid
(negatively charged at body pH)
Basic amino acids
Arginine, Lysine, Histidine
(His has no charge at body pH)
Arginine and Histidine are required during...
periods of growth.
Arginine and Lysine are increased in...
histones, which negatively bind negatively charged DNA.
In the urea cycle, amino acid catabolism results in...
the formation of common metabolites (pyruvate, acetyl-CoA) which serve as metabolic fuels.
Excess nitrogen (NH3) generated by the urea cycle are...
converted to urea and excreted by the kidneys.
Hyperammonemia can be either...
acquired (liver dz) or hereditary (urea cycle enzyme deficiencies).
Hyperammonemia results in excess...
NH4+ which depletes alpha-ketoglutarate, leading to inhibition of the TCA cycle.
Treatment for hyperammonemia
limit protein in the diet; benzoate or phenylbutyrate; lactulose
Ammonia intoxication symptoms
N-acetylglutamate deficiency is the...
lack of the required cofactor for carbamoyl phosphate synthetase I leading to hyperammonemia.
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.
The most common urea cycle disorder is..
ornithine transcarbamylase deficiency (x-linked). It interferes with the body's ability to eliminate ammonia.
Ornithine transcarbamylase deficiency is often evident in...
the first few days of life but may present with late onset.
In ornithine transcarbamylase deficiency, excess carbamoyl phosphate is converted to...
orotic acid (as part of the pyrimidine synthesis pathway).
Findings of Ornithine transcarbamylase deficiency
-increased orotic acid (in blood and urine)
-symptoms of hyperammonemia
-no megalosblastic anemia
Phenylketonuria is due to...
decreased phenylalanine hydroxylase or decreased tetrahydrobiopterin cofactor. Tyrosine becomes essential and increased phenylalanine leads to excess phenylketones in the urine.
Findings of PKU (6)
1. intellectual disability
2. growth retardation
4. fair skin
6. musty body odor
Treatment for PKU
-decrease phenylalanine and increase tyrosine in diet
Maternal PKU is when...
there is a lack of proper dietary therapy during pregnancy.
Findings in the infant from maternal PKU (4)
2. intellectual disability
3. growth retardation
4. congenital heart defects
PKU is screened for...
2-3 days after birth (they are normal at birth due to maternal enzyme).
The musty body order in PKU is because of ...
the disorder of ARAMATIC amino acid metabolism.
PKU pts must avoid...
the artificial sweetener aspartame, which contains phenylalanine.
Alkaptonuria is a...
congenital deficiency of homogentisate oxidase in the degradative pathway of tyrosine to fumarate.
Findings of alkaptonuria
dark CT, brown sclerae, urine turns black on prolonged exposure to air, debilitating arthralgia (bc homogentisic acid is toxic to cartilage)
3 Types of Homocystinuria
1. cystathionine synthase deficiency
2. decreased affinity of cystathionine synthase for pyridoxal phosphate
3. homocysteine methyltransferase deficiency
Cystathionine synthase deficiency should be treated with...
decreased methionine, increased cysteine and increased B12/folate in diet.
Decreased affinity of cystathionine synthase for pyridoxal phosphate should be treated with...
greatly increased B6 and cysteine in the diet.
Homocysteine methyltransferase (methionine synthase) deficiency should be treated with...
increased methionine in the diet.
Findings of Homocystinuria (8)
1. increased homocysteine in urine
2. intellectual disability
6. lens subluxation
8. atherosclerosis (stroke and MI)
Cystinuria is due to..
a hereditary defect of renal PCT and intesitnal amino acid transporter for Cysteine, Ornithine, Lysine, and Arginein (COLA).
Excess cystine in the urine can lead to...
precipitation of hexagonal cystine stones.
Diagnostic test for cystinuria is...
urinary cyanide-nitroprusside test.
Treatment for cystinuria
urinary alkalinization (w/ potassium citrate, acetazolamide)
and chelating agents (increase solubility of stones)
Maple syrup urine disease is...
blocked degradation amino acids (Isoleucine, Leucine, Valine) due to decreased alpha-ketoacid dehydrogenase (B1).
Maple syrup urine disease causes...
increaesed alpha-ketoacids in the blood, esp. of leucine.
Maple syrup urine disease leads to...
severe CNS defects, intellectual disability and death.
Treatment of maple syrup urine disease
restriction of leucine, isoleucine and valine in the diet and thiamine supplementation
Glycogen branches have...
alpha-(1,6) bodns and linkages have alpha-(1,4) bonds.
In skeletal muscle, glycogen....
undergoes glycogenolysis creating glucose-1-phosphate -> glucose-6-P which is rapidly metabolized during exercise.
In hepatocytes, glycogen is...
stored and undergoes glycogenolysis to maintain blood sugar at appropriate levels.
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.
"limit dextran" refers to...
the one to four residues remaining on a branch after glycogen phosphorylase has already shortened it.
A small amount of glycogen is degraded in lysosomes by...
alpha-1,4-glucosidase (acid maltase).
4 Glycogen Storage Diseases
1. Von Gierke Disease
2. Pompe Disease
3. Cori Disease
4. McArdle Disease
Findings of Von Gierke Disease
-severe fasting hypoglycemia
-increased glycogen in liver
-increased blood lactate
Deficienct enzyme in Von Gierke Disease
Treatment of Von Gierke Disease
frequent oral glucose/cornstarch; avoidance of fructose and galactose
Pompe Disease Findings
-cardiomyopathy leading to early death
Pompe Disease deficienct enzymes
-lysosomal alpha-1,4-glucosidase (acid maltase)
Cori Disease findings
-milder form of von gierke with normal blood lactacte levels
Cori Disease deficient enzyme
debranching enzyme (alpha-1,6-glucosidase)
(gluconeogenesis is intact)
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
McArdle Disease Deficient Enzyme
skeletal muscle glycogen phophorylase
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)
Lysosomal Storage Diseases (Mucopolysaccharidoses) (2)
1. Hurler Syndrome (AR)
2. Hunter Syndrome (XR)
Fabry Disease Findings
-peripheral neuropathy of hands/feet, angiokeratomas, CV/renal disease
Fabry Diseaes Deficient Enzyme
Fabry Disease Accumulated substrate
Gaucher Disease findings
-aseptic necrosis of femur
Gaucher cells are...
lipid-laden macrophages resembling crumpled tissue paper.
Treatment for Gaucher Disease is...
Gaucher Disease deficient enzyme
Gaucher diseas accumulated stubstrate
Niemann-Pick disease findings
-cherry red spot on macula
-foam cells (lipid-laden macrophages)
Niemann-Pick deficient enzyme
Niemann-Pick disease accumulated substrate
Tay-Sachs Disease findings
-cherry red spot on macula
-lysosomes with onion skin
Tay-Sachs deficient enzyme
Tay-Sachs accumulated substrate
Krabbe Disease findings
Krabbe disease deficient enzyme
Krabbe disease accumulated substrate
Metachromatic leukodystrophy findigns
-central and peripheral demyelination with ataxia
Metachromatic leukodystrophy deficient enzyme
Metachromatic leukodystrophy accumulated substrate
Hurler Syndrome findings
Hurler syndrome deficient enzyme
Hurler syndrome accumulated substrate
heparan sulfate, dermatan sulfate
Hunter Syndrome findigns
-mild Hurler + aggressive behavior
-no corneal clouding
Hunter syndrome deficient enzyme
Hunter syndrome accumulated substrate
heparan sulfate, dermatan sulfate
Ashkenazi Jews have increased incidence of...
Tay-Sachs, Niemann-Pick and Gaucher.
Long chain fatty acid degradation requires...
carnitine-dependent transport into the mitochondrial matrix.
Carnitine deficiency leads to an...
inability to transport LCFAs into the mitochondria, resulting in toxic accumulation.
Carnitine deficiency causes...
weakness, hypotonia and hypoketotic hypoglycemia.
Acyl-coA dehydrogenase deficiency findings
-increased dicarboxylic acids
-decreased glucose and ketones
In the liver, fatty acids and amino acids are metabolized to...
acetoacetate and beta-hydroxybutyrate (to be used in the muscle and brain).
In prolonged starvation and diabetic ketoacidosis, there is depletion of...
In alcoholism, there is excess...
NADH which shunts oxaloacetate to malate.
Both starvation/diabetic ketoacidosis and alcoholism cause...
a buildup of acetyl-CoA, which shunts glucose and FFA toward the production of ketone bodies.
Ketone bodies cause...
the breath to smell like acetone (fruity odor).
Urine test for ketones does not detect....
Fed state processes (3)
-insulin stimulates storage of lipids, proteins and glycogen
Fasting state processes (between meals) (4)
-adipose release of FFA
-glucagon and adrenaline stimulate use of fuel reserves
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
RBCs lack mitochondria so they cannot...
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
The rate limiting step of cholesterol synthesis is...
catalyzed by HMG-CoA reductase (induced by insulin) which converts HMG-CoA to mevalonate.
2/3 of plasma cholesterol is esterified by...
lecithin-cholesterol acyltransferase (LCAT).
Pancreatic lipase is for degradation of...
dietary triglycerides in the small intestine.
Lipoprotein lipase (LPL) is for...
degradation of TG circulatin gin chylomicrons and VLDLs. Found on vascular endothelial surface.
Hepatic TG lipase is for degradation of...
TG remaining in IDL.
Hormone-sensitive lipase is for...
degradation of TG stored in adipocytes.
esterification of cholesterol.
Cholesterol ester transfer protein (CETP) mediates...
transfer of cholesterol esters to other lipoprotein particles.
mediates remnant uptake
lipoprotein lipase cofactor
mediates chylomicron secretion
binds LDL receptor
Chylomicron apolipoproteins (4)
Chylomicron remnant apolipoproteins (2)
VLDL apolipoproteins (3)
IDL apolipoproteins (2)
LDL apolipoproteins (1)
HDL apolipoproteins (3)
Lipoproteins are composed of varying proportions of...
cholesterol, TGs, and phopholipids.
LDL and HDL carry most...
LDL transports cholesterol from..
liver to tissues.
HDL transports cholesterol from...
periphery to liver.
dietary TGs to peripheral tissue and cholesterol to the liver in the form of chylmomicron remnants.
Chylomicrons are secreted by...
intestinal epithelial cells.
hepatic TGs to peripheral tissues. Secreted by liver.
IDL is formed in..
the degradation of VLDL. Delivers TGs and cholesterol to the liver.
LDL is formed by...
hepatic lipase modification of IDL in the peripheral tissue.
LDL is taken up by target cells via...
HDL acts as a repository for...
apoC and apoE (which are needed for chylomicron and VLDL metabolism).
HDL is secreted from both...
liver and intestine. Alcohol increases the synthesis.
Hyperchylomicronemia (type I) has increased blood level of...
chylomicrons, TG and cholesterol.
Pathophysiology of hyperchylomicronemia
lipoprotein lipase deficieny or altered apolipoproteinC-II
pancreatitis, hepatosplenomegaly, and eruptive/pruritic xanthomas. (no increased risk of atherosclerosis)
Familial Hypercholesterolemia (type IIa) has increased blood levels of...
LDL and cholesterol.
Familial Hypercholesterolemia pathophysiology
absent or defective LDL receptors
(heterozygotes have cholesterol about equal to 300 and homozygotes have cholesterol about 700.
Familial hypercholesterolemia causes...
accelerated atherosclerosis (MIs before age 20), tendon xanthomas (Achilles), and corneal arcus.
Hypertriglyceridemia (type IV) has increased blood levels of...
VLDL and TG.