Biochemistry Flashcards
(200 cards)
1
Q
Chromatin structure
A
DNA loops twice around the histone OCTAMER to form a nucleosome (BEADS ON A STRING)
H1 histone binds to linker DNA
Euchromatin = less condensed Heterochromatin = condensed (more methylation and less acetylation)
2
Q
Charge of DNA
A
(+) due to lysine and arginine “its a (+) experience at dLA”
(-) Phosphate groups
3
Q
DNA methylation
Histone Methylation
Histone acetylation
A
DNA is methylated in imprinting ( DNA/histone epigenetic process that silences an allele without changing the DNA sequence)
Methylation of a gene promoter (CpG islands) typically represses gene transcription.
Histone methylation - reversible transcriptional suppression. But can also activate depending on where the methyl group is.
Histone acetylation - relaxes DNA coiling and active DNA
4
Q
Nucleotides
A
note: Nucleosides lack a phosphate but a nucleotide has a phosphate thats linked by a phosphodiester bond 3’-5’
more G-C bonds = higher melting temp
PURe As 2 Gold Rings - purines are adenine and guanine which has 2 rings
CUT 1 slice of Py - pyrimidines are cytosine, uracil, and thymine which have 1 ring
5
Q
Deamination products of nucleotides
A
Deamination is the process of losing a amino group
Cytosine –> uracil
Adenine –> hypoxanthine
Guanine –> xanthine
5-methylcytosine –> thymine
methylation of uracil makes thymine
6
Q
AA necessary for purine synthesis
A
Cats purr until they GAG (glycine, aspartate,glutamine)
7
Q
Purine synthesis
A
Ribose 5-P —– phosphoribosyl pyrophosphate (PRPP) synthase —> PRPP —> IMP –> AMP or GMP
de novo requires aspartate, glycine, glutamine, and THF
8
Q
Pyrimidine base production
A
Requires aspartate
CPS= carbamoyl phosphate synthetase
CPS1 = m1tochondria (ureal cycle). Deficiency causes hyperammonemia)
CPS2=cyTWOsol
Glutamine + CO2 —CPS2 and 2ATP–>carbamoyl phosphate
Carbamoyl phosphate + aspartate –> orotic acid
orotic acid + PRPP –> UMP (step is impaired in orotic aciduria)
UMP –> UDP –> dUDP OR CTP
UDP –ribonucleotide reductase —> dUDP –> dUMP –thymidylate synthase and THF —> dTMP + DHF
DHF is replenished via dihydrofolate reductase to reform THF which is used to make more dTMP
9
Q
A major cause of autosomal recessive SCID( severe combined immunodeficiency)
A
SCID - Disturbed development of functional T and B cells
Adenosine Deaminase Deficiency (ADA deficiency) - ADA is required for degradation of adensosine and deoxyadensosine. If deficient we have increase in dATP nucleotide which causes lymphotoxicity.
Adenosine –ADA–> Inosine –> –> uric acid –> excreted
10
Q
Purine salvage
A
refer to picture
11
Q
Patient presents with hyperuricemia (orange “sand” in diaper), gout, is pissed off/aggressive, self mutilation, retardation/intellectual disability, dystonia
A
Lesch-Nyhan syndrome is xlinked recessive
Defective purine salvage due to absent HGPRT (hypoxanthine guanine phosphoribosyl transferase) which is needed to convert hypoxanthine to IMP and guanine to GMP.
Accumulation of xanthine results in excess uric acid and de novo purine synthesis (from new rather than via salvage pathway)
Orange sand is sodium urate crystals
H-yperuricemia/uric acid accumulates in the brain G-out P-issed off/self mutilation/aggression R-etardation T-dysTonia
12
Q
Exception to the genetic code features
A
unambiguous
degenerate/redundant ( methionine/AUG and tryptophan/UGG are only encoded by 1 codon)
commaless/nonoverlapping ( Except in some viruses)
universal (except in mitochondria of humans)
13
Q
Promoters and origin of replication is rich in
A
AT sequences (i.e. TATA box regions)
14
Q
DNA topoisomerase
A
Creates a single or double stranded break in the helix to add or remove supercoils
15
Q
Primase
A
RNA primer for DNA pol III
16
Q
DNA polymerase III
A
Prokaryotes only
has 3’–>5’ exonuclease activity which proofreads
17
Q
DNA polymerase I
A
prokaryotes only
same as DNA pol III, exonuclease activity
degrade RNA primer and adds DNA
18
Q
Telomerase
A
Eukaryotes only
reverse transcriptase/RNA dependent DNA polymerase
adds DNA : TTAGGG to 3’ end of chromosomes
19
Q
Transition vs transversion
A
DNA mutation that is purine to purine vs purine to pyr (viceversa)
20
Q
What DNA mutation causes sickle cell disease
A
Missense mutation where glutamic acid is replaced with valine
21
Q
Nonsense mutation
A
early stop codon ( UAG, UAA, UGA) –> nonfunctional protein
22
Q
What DNA mutation causes Duchenne muscular dystrophy
A
Frameshift mutation affecting the DMD gene
Lacks functional dystrophin gene and cannot stabilize/protect mm fibers
23
Q
What DNA mutation causes Tay Sachs disease
A
Frameshift mutation
lack enzyme that breaks down fatty substance gangliosides which then build up in th brain and destroy the nervous system (motor deficit, blind, deaf)
24
Q
LAC operon
A
glucose is the preferred metabolic substrate in E. Coli. If glucose is absent but lactose available then lac operon is activated to switch to lactose metabolism.
low glucose –> increase in adenylate cylase activity –> increase generation of cAMP from ATP –> activation of catabolite activator protein (CAP) –> increases transcription
High lactose –> unbind repressor protein from repressor/operator site –> increases trancription
allolactose is an inducer that inactivates repressor
25
Xeroderma pigmentosum
autosomal recessive
defect in nucleotide excision repair during G1 phase- cannot repair DNA pyrimidine dimers caused by UV exposure
26
Base excision repair
Important in spontaneous/toxic deamination
Base specific Glycosylase removes altered base and creates AP site (apurinic/apyrimidinic)
AP endonuclease cleaves the 5' end
Lyase cleases the 3' end
DNA pol Beta fills gap
Ligase seals it
27
Lynch syndrome
Due to problem in mismatch repair during S phase
autosomal dominant
HNPCC- hereditary nonpolyposis colorectal cancer
Colon and endometrial cancers most common
28
Defect in ataxia telangiectasia and fanconi anemia
Defective nonhomologous end joining )bringint ogether 2 ends of DNA fragments to repair double stranded breaks. No requirement for homology. Some DNA lost
ataxia telangiectasia is progressive difficulty with coordinating movements
Fanconi anemia is impaired bone marrow function
29
Defect in BRCA1 mutation
homologous recombination - repair damaged strand sing a complementary strand from the intact homologous dsDNA as a template
30
mRNA start codon
AUG or rarely GUG
AUG - methionine in euk
AUG - N-formylmethionine(fmet) in prok
31
RNA polymerases (euk)
RNA I: rRNA (MOST common)
RNA II: mRNA
RNA III: tRNA
32
alpha- amanitin found in death cap mushrooms
Amanita phalloides mushrooms
inhibit RNA pol II (mRNA) and cause severe hepatotoxicity
33
RNA polymerase (prok)
one RNA pol makes 3 kinds of RNA
34
mRNA
DNA transcribed into hnRNA which is spliced into mRNA which is translated into proteins
capped with 7'-methylguanosine cap, spliced at 5' then 3', and poly A tailed transcript produced in the nucleus and then translated in the cytosol
polyadenylation signal = AAUAAA. Addition of 200 As at 3' end
Exons are EXPRESSED
35
microRNAs
noncoding RNA molecules that posttranscriptionally regulate gene expression by targeting the 3' untranslated region
36
tRNA structure
T arm (ribothymidine, pseudouridine, cytidine sequence) allows it to tether to the ribosome
D arm detects - (dihydrouridine residues) necessary for tRNA recognition by correct aminoacyl-tRNA synthetase
anticodon loop
acceptor stem - CCA at 3' end which then is covalently bound to the AA
aminoacyl-tRNA synthetase - 1 per AA, uses ATP to match
37
Protein synthesis initiation
euk initiation factors (eIFs) identify either the 5' cap or an internal ribosome entry site (IRES) at 5'-UTR--> help assemble 40S ribosomal subunit with initiator tRNA
Released when the mRNA and the ribosomal 60s subunit assemble with the complex
uses GTP
EUK: 40S + 60S --> 80S (EVEN)
PROK: 30S + 50S --> 70S (Odd)
tRNA charged with ATP
tRNA grips and translocates with GTP
38
Protein synthesis elongation
A site - incomin aminoacyl tRNA
P site - accomodates growing peptide
E site - holds empty tRNA as it exits
aminoacyl-tRNA binds to A site --> rRNA (ribozyme) catalyzes the peptide bond and transfers growing polypeptide to AA in A site
ribsome advances 3 spaces --> peptidyl tRNA now in P site
39
Protein synthesis termination
release factor recognizes stop codon
requires GTP to release
40
Cell cycle
regulated by cyclins, cyclin-dependent kinases (CDKs), and tumor suppressors
M phase --> G1(growth) or G0 --> S (DNA synthesis) --> G2
cyclin-CDK complexes must be activated/deactivated at appropriate times for cell cycle progression
41
tumor suppressors
P53--> induces P21 --> inhibits CDK --> hypophosphorylation of Rb/activates Rb --> inhibits G1-S progression
Defect can cause Li- fraumeni syndrome ( predisposition ot wide range of cancers)
42
growth factors
bind tyrosine kinase receptors to transition the cell from G1 to S phase
43
Cell types
permanent - G0
Stable/quiescent - G0 then to G1 when stimulated
Labile - never G0. always G1 (MOST affected in chemo)
44
RER vs SER
RER- secretory protein synthesis
SER- steroid synthesis and detox
45
Function of the Golgi
Modified N-oligosaccharides on asparagine
Adds O-oligosaccharides on serine and threomine
Adds mannose-6-phosphate to proteins for trafficking to lysososmes
46
Pt presents with coarse facial features, gingival hyperplasia, clouded corneas, restricted joint movements, claw hand deformities, kyphoscoliosis, and high plasma levels of lysosomal enzymes
I-Cell disease/ inclusion cell disease/ mucolipidosis type II - an inherited lysosomal storage disorder
defect in N-acetylglucosaminyl-1-phosphotransferase prevent phosphorylation of mannose residues and therefore a decrease in mannose-6-phosphate --> proteins excreted rather than delivered to lysosomes
47
Signal recognition particle (SRP)
traffics protein from the ribosome to the RER. if absent then protein accumulates in the cytosol
48
Vesicular trafficking proteins
COPI: golgi to golgi (retrograde). cis-Golgi to ER
COPII: ER --> cis-golgi (anterograde)
"two steps FORWARD.. 1 step BACK"
49
Peroxisome
- beta oxidation of very long chain FA
- alpha oxidation
- catabolism of branched FA, AA, and ethanol
- synthesis of cholesterol, bile acids, and plasmalogens
50
Zellweger syndrome
autosomal recessive
cerebrohepatorenal syndrome- caused by decreased peroxisome causing accumulation of lipids which impairs normal function of multiple organ systems
mutated PEX gene
hypotonia, seizures, hepatomegaly, early death
51
refsum disease
autosomal recessive
disorder of alpha oxidation in peroxisome
phytanic acid not metabolized to pristanic acid
scaly skin, cataracts,night blindness, shortening of 4th toe, epiphyseal dysplasia
tx with diet
52
adrenoleukodystrophy
xlinked recessive
disorder of beta oxidation in peroxisome --> build up of VLCFA (very long chain FA) in ADRENAL glands, white matter of brain (LEUKO), testes.
adrenal gland crisis, coma, and death
53
proteasome
barrel shaped protein complex that degreades damaged or ubiquitin-tagged proteins
implicated in parkinsons
54
microtubule
helical array of polymerized heterodimers of alpha and beta tubulin
each dimer has 2GTP bound
Positive end goes to the periphery
Negative end goes to the nucleus
dynein- retrograde to microtubule ( + --> -)
Kinesin- anterograde to microtuule (- --> +)
55
cilia structure
9 doublet + 2 singlet arrangement of microtubules
basal body (base of cilium below cell membrane) consists of 9 microtubule triplet with no central microtubule
axonemal dynein - ATPase that links peripheral 9 doublets and causes bending of cilium
56
pt presenting with decreased Male/Female fertility due to immotile sperm and dysfunctional fallopian tube cilia
kartagener syndrome (primary ciliary dyskinesia)
"kartagener's restaurant - take out only. theres no dynein "dine in""
can also cause bronchiectasis, recurrent sinusitis, chronic ear infections, conductive hearing loss, and situs inversus
57
N-K ATPase
1 ATP
3 Na out (phosphorylated)
2 K in (dephosphorylated)
ATP site on cytosolic side
58
Collagen
Type 1 - bONE
- decrease in osteogenesis imprefecta type 1
Type 2 - carTWOlage
Type 3 - reticulin - blood vessels
- decrease in Ehlers Danlos syndrome, vascular type
type 4 - floor (basement membrane)
- Alport syndrome ( kidney dz, hematuria, hearing
loss, eye abnormalities)
- goodpasture syndrome ( targeted by
autoantibodies, autoimmune dz where attack
basement membrane of kidneys and lungs)
59
Collagen synthesis
Collagen is 1/3 glycine
1) synthesis - pro alpha chain backbone [ Gly-X-Y] . X and Y are proline or lysine
2) hydroxylation of proline and lysine. This requires vitamin C. This is why a vitamin C deficiency causes scruvy
3) Glycosylation of hydroxylysine residues and formation of procollagen via H and disulfide bonds --> procollage is a triple helix of alpha chains. If cant form triple helix --> osteogenesis imperfecta
4) exocytosis of procollagen
5) cleavage of procollage at C and N terminals --> tropocollagen which is isnsoluble. Problems with cleavage causes Ehlers Danlos syndrome
6) formation of cross links between tropocollagen molecules by covalent lysine-hydroxylysine cross-linkage (by copper containing lysyl oxidase) to make colalgen fibrils. Problems with crosslinking causes ehlers danlos syndrome and menkes diseases (x linked recessive, impaired copper absorption and transport due to defective Menkes protein (ATP7A). Leads to decreased activity of lysyl oxidase and defective colalgen)
60
osteogenesis imperfecta
most commonly COL1A1 and COL1A2
autosomal dominant
patients that cant BITE
B- bones have multiple fractures
I- eyes have blue sclera
T- teeth have dental imperfections to due lack of dentin
E- Ear/hearing loss due to abnormal oscicles
61
Ehlers Danlos syndrome
hyperextensible skin, hypermobile joints, and tendeny to bleed (Easy bruising)
Most common type is hypermobile joint type
Classic type: joint and skin symptoms caused by mutation in type V collagen (COL5A1 and COL5A2)
Vascular type: type 3 procollagen deficiency (COL3A1 and COL3A2)
62
Pt presents with brittly kinky hair, growth retardation, and hypotonia
Menkes disease
x linked recessive
impaired copper absorption and transport due to defective Menkes protein (ATP7A). Leads to decreased activity of lysyl oxidase which needs copper as a cofactor --> defective collagen
63
Elastin
rich in nonhydroxylated proline, glycine, and lysine
crosslinking gives it its elastic properties
alpha1-antitrypsin 1 inhibits elastase and therefore elastin breakdown --> deficiency causes emphysema due to unopposed elastase activity
64
Marfan syndrome
MarFAN syndrome
autosomal dominant
FBN1 gene on chromosome 15 --> defective fibrillin ( a glycoprotein that forms sheats around elastin)
Skeletan, heart, and eyes
FAN - subluxation of lenses typically upwards and temporally. As if looking upward at a ceiling fan
65
PCR
denature by heating to 95
Anneal by cooling to 55. Add primers, a heat stable DNA polymerase like Taq and dNTPs
Elongonation by increase temp to 72 and DNA poly attache s to dNTPs to the strand
66
Blotting
SNoW DRoP
Southern - DNA
Northern - RNA
Western - Protein
Southwestern - DNA binding proteins
67
Flow cytometry
cells are tagged with antibodies specific to surface or intracellular proteins. Antibodies are then tagged with a unique fluorescent dye. Sample is analyzed one cell at a time by focusing a laser on the cell and measuring light scatter and intensity of fluorescence
68
Micro arrays
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 complementary binding
69
enzyme linked immunosorbent assay (ELISA)
immunologic test
Direct ELISA - a specific antigen
Indirect ELISA- antibody
antibody linked to an enzyme. added substrate reacts with enzyme and produces a detectable signal
70
Cas9/CRISPR
a genome editing tool derived from bacteria that allows removing, adding, or altering sections of the DNA sequence
Cas9 - endonuclease
gRNA - guide RNA sequence that binds to the complementary target DNA sequence
71
fluorescence in situ hybdrization
similar to karyotyping. except fluorescent DNA or RNA probes bind to specific gene ites of interest on chromsoomes. Each color represents a chromosome specific probe.
Detects microdeletions, translocation, duplications
72
Cre-lox system
can inducibly manipulate genes at specific developmental points
73
RNA interference
dsRNA is synthesized that is complementary to the mRNA sequence of interest.
Transfected into human cells, dsRNA separates and promotes degradation of target mRNA, "knocking down" gene expression
74
incomplete penetrance
% penetrance x probability of inheriting genotype = risk of expressing phenotype i.e. BRCA1
75
pleiotropy
one gene contributed to multiple phenotypic effects i.e. phenylketonuria
76
anticipation
increasing severity or earlier onset of disease in succeeding generations i.e. huntingtons
77
McCune Albright syndrome
Mosaicism example. lethal if affecting all cells. But survivable in patients with mosaicism
due to mutation affecting G protein signaling
Unilateral cafe-au-late spots with ragged edges
polyostotic fibrous dysplasia - bone replaced with collagen and fibroblasts
one endocrinopathy (i.e. precocious puberty)
78
Locus heterogeneity
Allelic heterogeneity
Heteroplasmy
locus heterogeneity - mutations at different loci can produce a similar phenotype (albinism)
Allelic heterogeneity - different mutations in the same locus produce the same phenotype (beta thalassemia)
Heteroplasmy - both normal and mutated mtDNA
79
Uniparental disomy
euploid/correct number of chromosomes
offspring gets 2 copies from 1 parent and no copies from other parent.
Heterodisomy - meiosis I error (heterozygous)
IsodIsomy - meiosis II error (homozygous)
in pt with recessive disorder when only one parent is a carrier.
I.e. angelman syndrome and prader willi
80
Hardy-weinberg
X linked recessive disease in males = q
in females = q^2
- no mutations at locus
- natural selection is not occuring
- completely random mating
- no net migration
81
Pt presents with hyperphagia, obesity, intellectual disability, hypogonadism, and hypotonia
Uniparental disomy --> Prader-Willi Snydrome
paternal allele is deleted or mutated on chromosome 15
Mother is silenced
82
Pt has inappropriate laughter (happy puppet), seizures, ataxia, and severe intellectual disability
Uniparental disomy --> angelman syndrome
Maternal UBE3A gene is deleted or mutated
Paternal is silenced
83
X linked recessive vs dominant
mostly sons affected and skips generations
vs
both parents can transmit. Mothers to 50% of sons and daughters. Fathers to all daughters no sons. (i.e. hypophosphatemic rickets- vit D resistant rickets. Increased phosphate wasting results in ricket like presentation, fragile X, alport syndrome
84
mitochondrial inheritence
mom to son or daughters
mitochondrial myopathies - myopathy, lactic acidosis, and CNS disease. secondary to failure in oxidative phosphorylation. MM fibers often show ragged red fibers due to accumulation of diseased mitochondria.
leber hereditary optic neuropathy - cell death in optic nerve neurons
85
Cystic Fibrosis
autosomal recessive
CFTR gene on chromosome 7
deletion of Phe508
decrease in Cl- secretion and H20 secretion. Increased intracellular Cl- causes compensatory increase in Na reabsorption via epithelial Na channels. Futher increases H20 reabsorption --> thick mucus secreted into lungs and GI tract
pilocarpine induced swear test is diagnostic. Newborn screening with increased immunoreactive trypsinogen. meconium ileus in children. infetility in men because have absent vas deferens
contraction alkalosis and hypokalemia
early infanct - s aureus
adolescence - p aeruginosa
86
x linked recessive disorders
Oblivious Female Will Often Give Her Boys Her x-Linked Disorders
```
O-ornithine transcarbamylase deficiency
F-Fabry disease
W-wiskott aldrich syndrome
O-ocular albinism
G-6PD deficiency
H-hunter syndrome
B-Bruton agammaglobulinemia
H-hemophilia A and B
L-lesch0nyhan syndrome
D-Duchenne and becker muscular dystrophy
```
87
Duchenne muscular dystrophy
Frameshift mutation in DMD--> absent dystrophin protein --> myofiber damage over time
onset before 5 yo
begins in pelvic girdle mm and progresses superioly
pseudohypertrophy of calve mm - fibrofatty replacement of mm
dilated cardiomyopathy is common cause of death
Gowers sign
88
Beckers muscular dystrophy
non-frameshift deletions in dystrophin gene
X-linked
adolescent onset
89
Pt presents with myotonia, mm wasting, cataracts, testicular atrophy, frontal balding, arrhythmia
"hatchet face" due to atrophy of temporalis mm and dropping mouth due to weakness of facial mm
Myotonic type 1
autosomal dominant
CTG repeat expansion in the DMPK gene
C- cataracts
T-toupe
G-gonadal arophy
90
pt is a 3 yo girl that has regression in her motor,verbal, and cognitive abilities. Also has wringing of her hands
Rett syndrome (RETTurn aka regression)
MECP2 on X chromosome
typically 1-4 yo girls because boys die in utero
motor,verbal, and cognitive abilities are regressing. Ataxia, seizures, growth failure, and stereotyped handwringing
91
pt presents with enlarged testes, long face, large jaw, large everted ears, autism, and a mitral valve prolapse
Fragile X syndrome
X lined dominany
CGG repeat during oogenesis in FMR1 gene --> hypermethylated --> decreased expression
Most common cause of inherited intellectual disability
2nd most common genetically associated mental deficiency (after Downs)
C - chin protruding
G - Giant
G - Gonads
92
Trinucleotide repeat expansion diseases
Tri HUNTING for My FRAGILE cage-FREE eggs (X)
1) Huntington disease (AD)- CAG repeat.
C-CAUDATE
A- decreased ACH and
G-GABA
2)Myotonic dystrophy (AD) - CTG repeat
C- Cataracts
T-Toupee
G-Gonadal atrophy
3) Fragile X (XD) - CGG
C-chin protruding
G-giant
G-gonads
4) Friedreich ataxia (AR) - GAA
ataxic GAAit
93
Downs Syndrome
trisomy 21 (mostly due to meiotic nondisjunction, if robertsonian translocation then due to chromosomes 14 and 21)
```
5 A's of Downs syndrome
A- advanced maternal age
A- Atresia (duodenal)
A- AV septal defect
A- Alzheimer disease early onset (chromosome 21 codes for amyloid precursor protein)
A-AML/ALL
```
94
Edwards syndrome
trisomy 18
PRINCE edward died at age 1
```
P-prominent occiput
R-rocker bottom feet
I-Intellectual disability
N-nondisjunction
C-clenched fists (with overlapping fingers)
E- Ears are low set
```
also: micrognathia (small jaw)
95
Patau syndrome
trisomy 13
think P=puberty=age 13
Cleft lip/palate, holoprosencephaly, polydactyly,cutis aplasia, polycystic kidney disease
death by age 1
96
Serum markers for Trisomy 21,18,13
first trimester: All low EXCEPT for 21 the beta-hCG is high
second trimester: All low except in 21 the beta-HCG and inhibin A are high. Everything normal in 13
97
Robertsonian translocation
long arms of 2 acrocentric chromosomes fuse at the centromere and the 2 short arms are lost
98
Cri-du-chat syndrome
congenital deletion on the short arm of chromosome 5
"cry of the 5 cats"
high pitches crying/meowing and cardiac abnormalities (VSD)
99
Williams syndrome
congenital microdeletion of long arm of chromosome 7
includes elastin gene
elfin facies, hypercalcemia (increased sensitivity to vit D), extreme friendiness with strangers
I watched WILL ferrel in Elf SEVEN times and he was FRIENDLY
100
22q11 deletion syndromes
Digeorge syndrome - thymic, parathyroid, and cardiac defects
Velocardiofacial syndrome - palate, facial, and cardiac defects
due to aberrant develpment of 3rd and 4th branchial (pharyngeal) pouches
```
CATCH 22
C- cleft palate
A-abnormal fascies
T-thymic dysplasia
C-cardiac defects
H-hypocalcemia secondary to parathyroid aplasia
```
101
fat soluble vitamins
ADEK
102
water soluble vitamins
```
B1 (thiamine -->TPP)
B2 (riboflavin --> FAD,FMN)
B3 (niacin --> NAD+)
B5 (pantothenic acid --> CoA)
B6 (pyridoxine --> PLP)
B7 (biotin)
B9 (folate)
B12 (cobalamin)
C (ascorbic acid)
```
All wash out of body except B12 (stored in liver for 3-4 yrs) and B9 (stored in liver for 3-4 months)
coenzymes or precursors
deficiency: dermatitis, glossitis, diarrhea
103
Vitamin A
retinol
- Constinuent of visual pigments
- Essential for normal differentiation of pancreatic and mucus secreting cells
- Prevents squamous metaplasia
Treats measles
Retin-A - wrinkles and acne med
Isotretinoin- cystic acne ( TERATOGENIC --> cleft palate and cardiac abnormalities. pt needs a negative pregnancy test and two forms of contraception)
trans retinoic acid to tx acute promyelocytic leukemia (APL)
104
Vitamin B1
thiamine
In thiamine pyrophosphate (TPP) - cofactor
ATP mnemonic -
A- alpha ketoglutarate dehydrogenase (TCA cycle)
T- Transketolase (HMP shunt)
P- pyruvate dehydrogenase (links glycolysis to TCA)
Deficiency causes impaired glucose breakdown and ATP depletion. Worsened by glucose infusion
Wernicke-karsakoff syndrome- Classic triad of confusion, ophthalmoplegia, ataxia
Dry Beriberi - polyneuropathy and symmetrical mm wasting
Wet Beriberi - high output cardiac failure (dilated cardiomyopathy) and edema
mnemonic : Ber1Ber1
dx: increased RBC transketolase following B1 administration
105
Vitamin B2
riboflavin
component of FAD and FMN (redox rxns)
mnemonic: fiboFlavin (Fad and Fmn)
B2= 2 ATP
deficiency: 2 Cs of B2 ( Cheilosis and Corneal vascularization)
106
Vitamin B3
niacin derived from tryptophan. requires B2 and B6 (6/2=3)
starts with N therefore NAD+ and NADP+(redox rxns)
B3= 3 ATP
Can be used to tx dyslipidemia by lowering levels of VLDL and raising levels of HDL
Deficiency? Pellagra (3 Ds: Diarrhea, Dementia, Dermatitis (broad collar rash). Also consider Hartnup disease
Excess? Podagra (gout of the foot)
107
Hartnup disease
AR
deficiency of neutral AA like tryptophan transporters on proximal renal tubular cells and enterocytes (cant make vitamin B3 --> pellagra like symptoms)
108
Vitamin B5
pantothenic acid
Coenzyme A (CoA) component. CoA is a cofactor for acyl transferase and FA synthase
109
Vitamin B6
pyridoxine
converted to pyridoxal phosphate (PLP) which is important for transamination, decarboxylation, and glycogen phosphorylase
110
Vitamin B7
biotin
cofactor for carboxylation enzymes
1) pyruvate carboxylase: pyruvate (3C)--> oxaloacetate (4C)
2) Acetyl-CoA carboxylase: acetyl-CoA (2C) --> malonyl-CoA (3C)
3) propionyl-CoA carboxylase: propionyl-CoA (3C) --> methylmalonyl-CoA (4C)
AVIDin in egg whites avidly binds biotin -> causes deficiency
111
Vitamin B9
folate --> tetrahydrofolic acid (THF)
folate from foliage
important for the synthesis of nitrogenous bases in DNA and RNA
give Vitamin B9 for the 9 months of pregnancy (atleast 1 month prior)
112
Vitamin B12
cobalamin
cofactor for methionine synthase (transfers CH3 goups as methylcobalamin) and methylmalonyl-coA mutase. important for DNA synthesis
refer to picture pathway
VERY large reserve in the liver. Deficiency usually cuased by malabsorption, lack of intrinsic factor, absence of terminal ileum, insufficient intake
antiintrinsic factor antibodies are diagnositc for pernicious anemia
(B9) Folate supplementation can mask the hematologic symptoms of B12 deficiency ( macrocytic, megaloblastic anemia etc) but not the neurologic symptoms. Prolonged deficiency causes irreversible nerve damage
113
Vitamin C
ascorbic acid
reduced iron to the Fe2+ state for absorption (can increase risk of iron toxicity when in excess)
necessary for hydroxylation of proline and lysine in collagen synthesis
necessary for dopamine Beta-hydroxylase (dopamine --> NE)
deficiency causes scurvy due to collagen synthesis defect
114
Vitamin D
```
D3= cholecalciferol (from sun)
D2 = ergocalciferol (from plants etc
```
D3 and D2 --> 24-OH D3 (storage form) in the liver
1,25-(OH)2D3 = calcitriol is the active form in the kidney
increases intestinal absorption of Ca and PO4, increase bone mineralization at low levels, increase bone resorption at higher levels
if increase in parathyroid hormone ( increase ca reabsorption and decrease phosphate reabsorption), drop in calcium and phosphate --> increase calcitriol production.
calcitriol will feedback inhibit its own production
Deficiency causes rickets and osteomalacia in adults
115
Vitamin E
tocopherol and tocotrienol
antioxidant that protects RBCs and membranes from free radical damage
high doses can alter vitamin K metabolism --> enhanced anticoagulant effects of warfarin
can present like B12 deficiency but without megaloblastic anemia, hypersegmented neutrophils, or increase serum methylmalonic acid levels
116
Vitamin K
phytomenadione, phylloquinone, phytonadione, menaquinone
synthesized by intestinal flora
activated by epoxide reductase to the reduced form. Which is a cofactor for gamma carboxylation of flutamic acid residues on various proteins required for blood clotting.
K is for Koagulation - necessary for maturation of clotting factors II, VII, IX, X and proteins C and S. Inhibited by warfarin
NOT in breast milk. given as injection at birth to prevent hemorrhagic disease of the newborn (with increased PT and aPTT but normal bleeding time). Neonates have sterile intestines and cannot synthesize vitamin K (also risk with prolonged broad spectrum antibiotic use)
117
Zinc
important for enzymes and zinc finger formation ( TF motif)
deficiency causes acrodermatitis enteropathica
118
Kwashiorkor
protein deficient MEALS
M-malnutrition
E-edema (decreases plasma oncotic pressure)
A-anemia
L-Liver malfunction (fatty change due to decreaed apolipoprotein synthesis)
S-skin lesions (hyperkeratosis, dyspigmentation)
119
Marasmus
Muscle wasting
No edema
calorie deficient
120
metabolism site - mitochondria
```
Beta oxidation (FA)
acetyl CoA production
TCA cycle
Oxidative phosphorylation
Ketogenesis
```
121
metabolism site - cytoplasm
Glycolysis
HMP shunt
Synthesis of steroids, proteins, FA, cholesterol, and nucleotides
122
Metabolism site - both mitochondria and cytoplasm
HUGs take two
Heme synthesis
Urea Cycle
Gluconeogenesis
123
Rate determining enzyme: glycolysis
Phosphofructokinase-1 (PFK 1)
+ AMP, F-2,6-BP
- ATP, Citrate
124
Rate determining enzyme: gluconeogenesis
Fructose-1,6-bisphosphate
+ citrate
- AMP, F-2,6-BP
125
Rate determining enzyme: TCA cycle
Isocitrate dehydrogenase
+ ADP
- ATP, NADH
126
Rate determining enzyme: glycogenesis
Glycogen Synthase
+G6P, insulin, cortisol
- Epi, glucagon
127
Rate determining enzyme: Glycogenolysis
Glycogen phosphorylase
+ epi, glucagon, AMP
- G6P, insulin, ATP
128
Rate determining enzyme: HMP shunt
Glucose-6-phosphate dehydrogenase (G6PD)
+ NADP
- NADPH
129
Rate determining enzyme: de novo pyrimidine synthesis
Carbamoyl phosphate synthetase II
+ ATP, PRPP
- UTP
130
Rate determining enzyme: de novo purine synthesis
Glutamine- phosphoribosylpyrophosphate (PRPP) amidotransferase
- AMP, inosine monophosphate (IMP), GMP
131
Rate determining enzyme: Urea cycle
Carbamoyl phosphate synthetase I
+ N-acetylglutamate
132
Rate determining enzyme: FA synthesis
acetyl-CoA carboxylase (ACC)
+ Insulin, citrate
- glucagon, palmitoyl-coA
133
Rate determining enzyme: FA oxidation
CArnitine acyltransferase I
- malonyl-coA
134
Rate determining enzyme: ketogenesis
HMG CoA synthase
135
Rate determining enzyme: cholesterol synthesis
HMG CoA reductase
+insulin, thyroxine
-glucagon, cholesterol
136
ATP production (aerobic, anaerobic)
aerobic - 1 glucose --> 32 ATP (heart and liver, malate-aspartate shuttle) or 30 ATP ( muscles, glycerol-3-phosphate shuttle)
anaerobic- 1 glucose --> 2 net ATP
137
Universal electron acceptors
NAD+ - catabolic
| NADPH- anabolic (HMP shunt)
138
Hexokinase vs glucokinase
Glucokinase: to store glucose in the liver and beta cells of the pancrease. It has low affinity and high capacity. Induced my insulin . Not feedback (-) by G6P
Hexokinase- sequesters glucose in tissues. Most tissues except liver and beta cells of pancrease. High affinity and low capacity. Not induced by insulin and is feedback inhibited by G6P
139
Km and Vmax
low Km = high affinity
| low Vmax= low capacity
140
pyruvate dehydrogenase complex
pyruvate + NAD + CoA --> acetyl CoA + CO2 + NADH
3 enzymes that require 5 cofactors
"The Lovely Coenzyme for Nerds"
```
T- Thiamine pyophosphate (B1)
L- Lipoic acid (This is inhibited by arsenic--> skin changes,vomiting, diarrhea, QT prolongation, garlic breath
C-CoA (B5, pantopenthic acid)
F-FAD (B2, Riboflavin)
N- NAD (B3, niacin)
```
SAME for alpha-ketoglutarate dehydrogenase complex in TCA cycle
Deficiency causes buildup of pyruvate --> increase in lactate or alanine
141
TCA cyle product
3 NADH, 1 FADH2, 2CO2, 1 GTP for eaach acetyl-coA
10 ATP per acetyl coa (x2 everything per glucose)
142
electron transport chain complexes
```
complex I - NADH
Complex II (succinate dehydrogenase)- FADH2
Complex III
complex IV
Complex V (ATP synthase)
```
143
ATP produced by ATP synthase
1 NADH --> 2.5 ATP
| 1 FADH2 --> 1.5 ATP
144
gluconeogenesis
primarily in the lvier
| mm cannot participate because lacks G6phosphatase
145
HMP shunt
NADPH source --> reductive rxns
Also ribose for nucleotide synthesis
Oxidative and non oxidative phases both occur in cytoplasm
No ATP used or produced
146
glucose-6-phosphate dehydrogenase deficiency
NADPH is necessary to keep glutathione reduced --> detox
low NADPH --> decreases RBC defenses --> hemolytic anemia
Heinz bodies- denatured globin chains ppt within RBCs due to oxidative stress
Bite cells --> phagocytic removal of heinz bodies by splenic macrophages
147
Essential fructosuria
defect in fructokinase
| KINASE is KIND - benign fructose in blood and urine
148
Hereditary fructose intolerance
deficiency in aldolase B
accumulation of F-1-P --> decrease phosphate --> inhibit glycogenolysis and gluconeogenesis
hypoglycemia, jaundice, cirrhosis
149
Galactokinase deficiency
deficiency in galactokinase causes accumulation of galactitol
galactosemia, galactosuria
failure to track objects or to develop a social smile
KINASE IS KIND
150
classic galactosemia
absence of galactose-1-phosphate uridyltransferase
toxic substances accumulate in the eye
symptoms develop when infant begins feeding
151
lactose
galactose +glucose
152
Sorbitol
alternative method of trapping glucose in the cell is to convery it to sorbitol via aldose reductase (Retina, Kidneys, Schwann cells)
Liver, ovary, and seminal vesicles can convert it to fructose via sorbitol dehydrogenase
153
LActase
digests lactose into glucose and galactose
154
essential AA
```
PVT TIM HaLL
P-phenylalanine
V-valine
T-Tyrosine
T-THreonine
I-Isoleucine
M-methionine
H-histidine
L-leucine
L-lysine
```
155
Glucogenic AA
Met His Sweet Valentine
M- methionine
H-Histidine
V-Valine
Sweer- glucogenic
156
Glucogenic AA/Ketogenic
TTIP
Threonine
Tyrosine
ISoleucine
Phenylalaine
157
Basic AA
His Lys Are Basic
Histidine
Lysine
Arginine
158
Asterixis is a sign of
Hyperammonemia/ammonia accumulation
Excess NH3 depletes glutamate (GABA) in CNS and alpha ketoglutarate --> inhibits the TCA cycle
Tx by limiting protein in diet
159
Ornithine transcarbamylase deficiency
Urea cycle disorder
cant eliminate ammonia
excess carbamoyl phosphate --> orotic acid (pyrimidine synthesis)
160
2 week old baby with musty body odor
phenylketonuria
due to decrease in phenylalanine hydroxylase or tetrahydrobiopterin (BH4) cofactor (mlaignant OKU)
Screen babies 2-3 days after birth because normal at birth due to maternal enzyme during fetal life
phenyl ketons: phenylacetate, phenyllactate, and phenyl pyruvate
disorder of AROMATIC AA metabolism therefore a musty body AROMA
must avoid artificial sweetner aspartame
tx with BH4 and tyrosine.
Can also have maternal PKU- due to lack of proper dietary therapy --> microcephaly, intellecual disability etc in baby
161
Urine smells like burnt sugar
Maple syrup urine disease
Blocked degradation of branched AA (Isoleucine, leucine, and Valine) due to decrease in branches chain alpha-ketoacid dehydrogenase (B1)
Causes increase in ketoacids ESPECIALLY leucine
tx with restriction of branched AA in diet and give thiamine (B1) supplementation
"I Love Vermont maple syrup from B1-ranches of the tree"
162
bluish black CT, sclera, and black urine after prolonged exposure to air
Alkaptonuria
deficiency of homogentisate oxidase in the degradative pathway of tyrsosine for fumarate --> homogentisic acid accumulates in tissues (black pigment)
also homogentisic acid is toxic to cartilage --> arthralgia
163
Homocystinuria
excess homocysteine
HOMOCYstinuria
```
Homocystein in urine
Osteoperosis
Marfanoid habitus
Ocular changes (down and in VS up and fan out in Marfan)
CV effects --> stroke or MI
kYphosis
```
164
Cystinuria
Cystine, Ornithine, Lysine and Arginine (COLA)
recurrent hexagonal cystine stones (cystine is two cysteines connected by a disulfide bond)
tx by alkanization of urine and chelating agents
165
Glycogen
branches have alpha- (1,6) bonds
| Linkages have alpha-(1,4) bonds
166
Steps to glycogenolysis
In skeletal mm : --> G1P--> G6P --> metabolized in excercise
in hepatocytes: glycogen is stored and is used to maintain blood sugar at appropriate levels
branched glycogen (some degraded in lysosome only)
--> glycogen phosphorylase frees up G1P residues off branches glycogen until only 4 units remain (limit dextrin)
-->4-alpha-D-glucanotransferase is the debranching enzyme and removed 3 of the 4 G1P
--> alpha-1,6-glucosidase is a debranching enzyme that cleaves the last G1P
--> GLUCOSEEE
167
Glycogen storage diseases
Very Poor Carb Metabolism
V-von gierke disease (type 1)
P-Pompe disease (type 2)
C- Cori disease (type 3)
M - McArdle disease (type 4)
168
Von Gierke Disease
Type I glycogen storage disease
deficient in glucose-6-phosphatase and therefore cannot break down glycogen
increase in glycogen in liver and kidneys
Increase in uric acid --> gout
169
Pompe disease
Type II glycogen storage disease
deficient in lysosomal acid alpha-1,4-glucosidase with alpha-1,6-glucosidase activity (Acid maltase)
Heart defects
Liver (hepatomegaly)
Muscle myopathy
170
Cori disease
Type III glycogen storage disease
milder form of type I
deficient in debranching enzyme alpha-1,6-glucosidase
171
McArdle disease
think M=Muscle (glycogen build up) --> cramps and myoglobinuria (Red urine with exercise)
deficient in skeletal mm glycogen phosphorylase (Myophosphorylase)
hallmark sign: flat venous lactate curve with normal rise in ammonia levels during exercise
172
Sphingolipidoses
lysosomal storage disease - lipid storage disorders relating to sphingolipid metabolism
Tay-sachs disease
Fabry Disease
Metachromatic leukodystrophy
Krabbe disease
Gaucher disease
Niemann-Pick disease
173
Tay Sachs disease
tAy-saX lacks heXosaminidase A
build up GM2 ganglioside
neurodegeneration
"cherry red" spot on the macula
NO hepatosplenomegaly
Onion skin lysosomes
lysosomal storage disease - lipid storage disorders relating to sphingolipid metabolism
174
Fabry disease
alpha-galactosidase A deficient
build up ceramide trihexoside
triad: episodic peripheraly neuropathy, angiokeratomas, hypohidrosis
lysosomal storage disease - lipid storage disorders relating to sphingolipid metabolism
175
Metachromic leukodystrophy
Lack arylsulfatase A
build up of cerebroside sulfate
central and peripheral demyelination --> dementia and ataxia
lysosomal storage disease - lipid storage disorders relating to sphingolipid metabolism
176
Krabbe disease
Deficient in galactocerebrosidase
build up of galactocerebroside and psychosine
peripheral neuropathy and progressive damage to nervous system
Globoid cells
lysosomal storage disease - lipid storage disorders relating to sphingolipid metabolism
177
Gaucher disease
Most common
deficient in glucocerebrosidase
build up of glucocerebroside
Gaucher cells - lipid laden macrophages resembling crumpled tissue paper
lysosomal storage disease - lipid storage disorders relating to sphingolipid metabolism
178
Niemann-Pick disease
"no man picks his nose with his spinger"
deficient in sphingomyelinase
build up of sphingomyelin
Neurodegenration
Cherry red spot on macula
Foam cells (lipid laden macrophages)
HAS hepatosplenomegaly (compared to tay sachs)
lysosomal storage disease - lipid storage disorders relating to sphingolipid metabolism
179
ashkenazi jews
tay sachs
niemann pick
gaucher
180
Mucopolysaccharidoses
disorder that results in the buildup of glycosaminoglycans (formerly known as mucopolysaccharides)
type 1: Hurler syndrome - deficient in alpha-L-iduronidase. Corneal clouding
type 2: Hunter syndrome - deficient in iduronate-2-sulfatase
"hunters see clearly and aim for the X" --> x linked recessive and no corneal clouding. Mild hurler + aggressive behavior
both accumulate herparan sulfate and dermatan sulfate
181
FA synthesis and break down
synthesis: citrate (" SYtrate=Synthesis")
Degradation: Carnitine ("CARnitine=CARnage")
Hypoketotic hypoglycemia
systemic primary carnitine deficieny - cant transport LCFAs into mitochondria --> toxic accumulation
Medium chain acyl coA dehydrogenase deficieny- cant break down FA into acetyl coA --> accumulation of fatty acyl carnitine
182
Ketone bodies
acetone, acetoacetate, beta hydroxybutyrate
In the liver:
FA and AA --> acetoacetate and beta hydroxybutryrate --> to use in mm and brain
in starvation and diabetic ketoacidosis: oxaloacetate is depleted for gluconeogenesis
Alcoholism: excess NADH shunts oxaloacetate to malate
BOTH cause buildup of acetly coA --> shunts towards production of ketone bodies
HMG coA lyase is used to ketone production
183
Calories in carb, alcohol, fatty acid
carb = 4
alcohol= 7
Fatty acid=9
184
starvation
day 1: glycogen reserves depleted
RBC lack mitochondria and cannot use ketons
after day 3: adipose stores and used until depleted then protein degradation accelerates
185
Lipid transport
1) chylomicron enter lymphatics
2) HDL transfers APO CII and ApoE to he chylomicron
3) the APO CII can activate Lipoprotein lipase
4) FFA enters adipocytes and chylomicron remnant to hepatocytes
____
1) Liver releases VLDL(APO B100)
2) HDL transfers APO CII and APO E to VLDL
3) APO CII activates lipoprotein lipase
4) FFA enter adipocyte and IDL remains
5) IDL delivers to liver via APOE
___
1) LDL released from hepatocyte
2) endocytosis of LDL by peripheral cells
186
Hepatic lipase
degrades TGs --> IDL
187
Hormone sensitive lipase
degrades TGs stored in adipocytes
188
Lecithin-cholesterol acyltransferase
catalyzes esterification of 2/3 of plasma cholesterol
nascent HDL --> mature HDL
APO AI activates
189
Apo E
EVERYTHING Except LDL
mediates remnant uptake
190
APO CII
chylomicron, VLDL, HDL
catalyzes lipoprotein lipase cleavage
191
B48
chylomicron, chylomicron remnant
mediates secretion into lyphatics
192
B100
VLDL,IDL, LDL
binds LDL receptor
only liver originating particles
193
VLDL
heptic Tgs --> peripheral tissues
194
LDL
hepatic cholesterol --> peripheral tissues
formed by hepatic lipase modification of IDL
195
HDL
cholesterol from periphery --> liver
196
Abetalipoproteinemia
chylomicrons, VLDL, LDL absent
Deficient in APOB48. APO B100
severe fat malabsorption
197
Type I - hyperchylomicronemia
LPL or APO CII deficieny
increases chylomicrons, TC, cholesterol in blood
Pancreatitis, hepatosplenomegaly, eruptive/pruritic xanthomas, NO increased risk for atherosclerosis
198
Type II - familial hypercholesterolemia
LDL receptors or APO B100 defective
increase LDL, cholesterol levels in IIa
iib also has increases VLDL
```
accelerated atherosclerosis
Tendon xanthomas (achilles)
```
199
Type III - Dysbetalipoproteinemia
Defective ApoE
chlymocrons and VLDL increase in blood
premature atherosclerosis
tuberoeruptive xanthomas
palmar xanthomas
200
Type IV- hypertriglyceridemia
Hepatic overproduction of VLDL
Increases blood levels of VLDL and TG
Hyperriglyceridemia (>1000 mg/dL)
related to insulin resistance
