Biochem Flashcards
2,3 - BPG binding site/type
ionic bond with Beta subunit of HgbA
high methionine = which aa now essential
which enzyme def
name
cysteine
defect in cystathione synthetase
homocystinuria
Lens sublixation down and in
homocysteinuria
Lens sublixation upward
Marfans
Enzyme def in homocysteinuria and tx(2)
- Cystathionine synthase (with B6)
tx: cysteine, up up B6 - homocysteine methyl transferase (?aka methionine synthase)(with B12)
tx: methionine, B12
symp homosysteinuria
intellectual dis osteoporosis TALL stature lens sublixation (down and in) thromosis atherosclerosis (MI, stoke)
homeless, increased fatigability, exertional dsypnea, LE edema, cardiac dilation, increased CO… nutrient def
B1 (thiamine)
wrinkles - cause
decreased collagen fibril production - net loss of dermal collagen and elastin
RNA between 74 and 93 nucleiotides
tRNA
*contains unusual nucleosides such as pseudouridine and thymidine
3’ end of tRNA
- CCA sequence (recognition sequence by proteins)
- terminal OH
- binding site for aa
acceptor stem of tRNA
3’/5’ ends
enzyme that catalyzes loading of tRNA with aa
aminoacyl tRNA sythetase
D arm of tRNA
lots of dihydrouracil residues
T arm of tRNA
contains sequence necessary for binding to ribosomes - thymidine, pseudouridine, cytidine
RNA containing thymidine
tRNA
5’ end of tRNA
terminal phosphate
larger protein, altered fx, retained immune reactivity - type of mt?
spice site mutation
vitamin tx for measles
vit A
Dermatitis, Diarrhea, ….
Niacin def
Child with ataxia, pruritic skin lesions, loose stools + netural aromatic aas in urine
Hartnup:
imparied instinal and renal absorption of tryptophan
tryptophan:
niacin, serotonin, melatonin
precursor of the NAD+ coenzyme
tryptophan
skin blisters, increased plasma porphyrins… enzyme?
uroporphyrinogen decarboxylase
human enzyme that has reverse transciptase
telomerase
subperiosteal hemotomas
scurvy - ascorbic acid/vit C def
cytoplasmic p bodies
role in mRNA translation regulation and mRNA degredation
snRNPs participate in function of…
spliceosomes
pyruvate dehdrogenase: which aa can you supplement safetly; why
lycine and leucine
- exclusively ketogenic and will not increase blood lactate levels
pyruvate dyhdrogenase: fx
pyruvate –> acetyl CoA
pyruvate dehdrogenase: cofactors
"TLC For Nobody" Thyamine pyrophsophatase (B1) Lipoic Acid Co-enzyme A (B5) FAD (B2) NAD+ (B3)
What uses the same cofactors as PDH
alpha KG dehydrogenase
What B vitamins are cofactors for PDH and alpha-KG dehydrogenase
B1 (thiamine)
B2 (riboflavin)
B3 (niacin)
B5 (panthenoic acid/panthenate)
arsenic poisoning MOA/symp
blocks lipoic acid (cofactor of PDH and alpha-KG dehrogenase)
Sx:
garlic breath
rice water stool
vomiting
alpha-KG dehdrogenase fx
alpha-kg –> succinyl-CoA (TCA cylcle)
PDH complex def symp
- build up of pyruvate gets shunted to lactate (via LDH) –> lactic acidosis
- neurologic defects
- high levels of serum alanine starting in infancy
PDH def congenital (geneics)
X-linked
PDH def tx
increase ketogenic nutirents (high fat content or increased lysine and leucine)
What are the 2 fates of pyruvate in the cytosol? (and via which enzymes/cofactors)
Cytosol:
Alanine
- via alanine aminotransferase (B6)
- carries amino groups to the liver from muscle
- Cahill cycle
Lactate
- via LDH (B3)
- end step of anaerobic glycolysis
- Cori cycle
What are the 2 fates of pyruvate in the mitochondria (and via which enzymes/cofactors)
Mitochondria:
Oxaloacetate
- via pyruvate carboxylase (biotin)
- addition of CO2 and ATP
- can replenish TCA cycle or used in gluconeogenesis
Acetyl CoA
- via PDH (B1, B2, B3, B5, lipoic acid)
- transition from glycolisis to TCA cyle
where is anaerobic glycolysis major pathway (6)
RBCs Leukocytes Kidney medulla Lens Cornea Testes
Potassium channel position when increased glucose (…)
CLOSED
- in response to increased ATP (from glucose met)
- -> depolarization –> open Ca channels–> exocytosis)
B6 deficiency: impairments in what conversion of pyruvate
pyruvate –> oxaloacetate
Biotin (B6) - roles
- CO2 carrier on carboxylase (e.g. pyruvatec carboxylase)
- decarboxylase rxs
- glycogen phosphorylase
- transamination (ALT, AST)
- conversion of aa precursors
(histamine, serotonin, epi, NE, DA, GABA) - synthesis of cystathionine, heme, niacin
Enzyme directly responsible for early lens opacities
Aldose reductase
insulin receptor cascade
tyrosine kinase –>
phosphorylation of insulin receptor substates–>
activation of protein phosphatase –>
(1) dephosphorylates glycogen synthase –>
(glycogen synthase activated) –>
increase glycogen synthesis
(2) dephosphorylates F-1,6-biphosphatase –>
(inactivated) –>
inhibids gluconeogenesis
JAK protein kinase
second messenger system for peptide hormones such as some cytokines in JAK-STAT pathway (signal transducers and activators of transcription)
has tyrosine kinase activity; receptor does NOT have INTRINSIC tyrosine-kinase activity - i.e. - tyrosine-kinase ASSOCIATED receptor
Fuels post-absorbative
brain and muscles/other tissues
All: glucose
When does gluconeogenesis begin?
When is it fully active?
(hrs after last meal)
4-6 hrs - begins
10-18 hrs - fully active (glycogen depleted)
Glycogen depleted (hrs)
10-18 hrs
Fuel 24 hrs after last meal
Brain:
glucose
Muscles/other tissues:
FA
(some glucose)
Fuel 48 hrs after last meal
Brain:
glucose
(some ketone bodies)
Muscles/other tissues:
FA
(some ketone bodies)
Fuel 5 days after last meal (prolonged starvation)
Brain:
ketone bodies
Muscles/other tissues:
FA
(some ketone bodies and a little glucose)
Overnight fast-
what percentage of energy comes from glucose and from ketone bodies
Overnight:
90% glucose (2/3 gycogen, 1/3 gluconeogenesis)
5% ketone bodies
3 day fast-
what percentage of energy comes from glucose and from ketone bodies
3 day fast:
60% ketone bodies (1/2 beta-hydroxybutyrate, 1/2 acetoacetate)
40% glucose (gluconeogen)
What metabolic scenario favors synth of ketone bodies
production of acetyl CoA from B-oxidation
exceeds
oxidative capacity of the TCA cycle
What cells cannot use ketone bodies
RBCs
- can only use glucose
Primary energy source in a pt that has not eaten in two days
FAs
Rate limiting step of ketone body synth
HMG CoA Synthase
Etoh –> hypoglycemia
- etoh metab increases NADH
- pyruvate –> lactate and oxaloacetate –> malate used to regenerate NAD+
- depleted substates for gluconeogenesis
insulin receptor structure
tetramer:
2 alpha - extracellular binding
2 beta - intracellular signalling (contain tyrosine kinase domains)
TNF alpha insulin resistance mech
TNF alpha activates serine kinases –>
1) phosphorylate IRS-1 serine residues –>
inhibits IRS-1 tyrosine phosphorylation by insulin
2) phosphorylates serine residues in beta subunit of insulin
note: phosphorylation of threonine resides has similar effects
What increases insulin resistance via phosphorylation of serine or threonine residues
TNF-alpha catecholamines glucocorticoids glucagon (maybe intracellular FFAs)
NE –> Epi
-PNMT
(phenylethanolamine-N-methyltransferase)
- PNMT transcription increased by CORTISOL
- occurs mostly in adrenal medulla (unlike DA and NE - produced in cetral and peripheral nervous system)
enzyme tyrosine –> DOPA
tyrosine hydroxylase
enzyme DOPA –> dopamine
dopamine decarboxylase
enzyme dopamine –> NE
dopamine beta-hydroxylase
enzyme NE –> Epi
PNMT
pheylethanolamine-N-methyltransferase
Use receptor tyrosine kinase?
Signalling pathway
Growth FACTOR receptors: - EGF - PDGF - FGF (etc)
MAP-kinase
Ras
Use tyrosine-kinase associated receptor
Signalling pathway
Receptors for: cytokines GH PRL IL-2
JAK/STAT
Liver enzyme - TG breakdown products –> glucose precursor
glycerol kinase
glycerol –> glyceral 3-phosphate
(glycerol 3-phosphate –> DHAP –> (1) glycolysis or (2) gluconeogen
Rate limiting step of HMP shunt (pentose phosphate pathway)
Glucose-6-P dehydrogenase
Enzyme in oxidative (irreversible) phase of HMP shunt
G6PD
Enzyme in nonoxidative (rervserible) phase of HMP shunt
Phosphopentose isomerase, transketolases
Sites of HMP shunt
CYTOPLASM of RBCs and sites of fatty acid or steroid synth: - lactating mammary glands - liver - adrenal cortex
Purpose of HMP shunt
- provide source of NADPH from G6P
- yields ribose for nucleotide sythesis and glycolitic intermediates
NADPH uses
- synth of FA and cholesterol
- GENERATION of oxygen free rad
- PRODECTION of RBCs from oxygen free rad
- cytochrome p450
hormones that act through g-protein receptors
glucagon TSH PTH LH FSH (all Gs (?) - work through adenylate cylcase--> cAMP --> protein kinase A)
alpha subunit of g-protein receptor’s response to stimulation
release of GDP;
binding of GTP –>
dissociation of alpha subunit
rate limiting step in FA degredation and where is it located
CAT - 1
(carnitine acyl transferase 1)
(aka carnitine palmitoyl transferase 1)
cytoplasm of mitochondria?
What is the shuttle in FA degredation
carnitine
What is the shuttle in FA synth
citrate
What is the rate limiting step in FA synth
acetyl- CoA carboxylase
Nonpolar, hydrophobic amino acids
valine alanine isoleucine methionine phenylalanine
alpha helix of 20 aa
transmembrane region
aldolase B def
- what should be removed from diet
fructose
sucrose (fructose+glucose)
aldolase B def - mechanism
phosphate trapping in fructose 6 phosphate
fructose –> frucotse 1-P
fructokinase
fructose 1-P –> glyceraldehyde or DHAP
aldolase B
bypasses rate limiting step of glycolysis (PFK)
fructose
DHAP –> F-1,6-BP
and
Glyceraldehyde-3-P –> F-1.6-BP
Muscle:
Aldolase A
Liver:
Aldolase B
Aldolase B def
Fructose intolerance
Fructokinase def
Essential fructosuria
positive gibs free energy favors…
reactants/substrates
cortisol receptor location
cytosol
Mcardle disease enzyme
myophosphorylase (muscle glycogen phosphorylase)
Cori disease enzyme
Debranching enzyme (1-6 glucosidase)
maybe debranching enzyme transferase
von Gierke disease enzyme
Glucose-6-phosphatase
Pompe disease enzyme
Acid alpha gucosidase
acid maltase
mild hyperglycemia exacerbated by pregnancy (enzyme inactive)
glucokinase:
glucose sensor within pancreatic beta cells
acetoacetyl-CoA –> 3-hydroxy-3-methylglutaryl CoA
pathway
synthesis of cholesteral and ketone bodies
vomiting, lethargy, failure to thrive soon after beginning breastfeeding
Classic galactosemia:
galactose-1-phosphate uridyl transferase
infant not tracking objects; lack of social smile
enzyme def
galactokinase deficiency
Thyroid hormone receptor
nuclear receptor
Retinoids receptor location
nucelar receptor
PPAR receptor location
peroxisomal proliferating activated receptors
nucleus
FA receptor locations
nucleus
Pyruvate carboxylase
location
pathway
action
mitochondria
gluconeogenesis
pyruvate –> oxaloacetate
Ornithine transcarbamoylase
location
pathway
action
mitochondria
urea cycle
ornithine + carbamoyl phosphate –> citrulline
succinate dehdrogenase
location
pathway
action
mitochondria
TCA cycle
succinate–> fumarate
3-hydroxy-3mthyglutaryl-CoA lyase
location
pathway
action
(HMG CoA lyase)
mitochondria
ketogenesis from HMG CoA
(HMG CoA from degradation of leucine or synth from HMG CoA synthase)
removal of pitutitary –> decreased epi
what enzyme act is decreased?
Pheylethanolamine-N-methyltransferase (PNMT)
allosteric activator of pyruvate carboxylase
Acetyl CoA
increases gluconeogenesis
sorbitol end product
fructose
glucose –> sorbitol
aldose reductase
NADPH –> NADP+
sorbitol –> fructose
sorbitol dehydrogenase
NAD+ –> NADH
cells with particularly active polyol pathway
(glucose-sorbitol-fructose)
seminal vesicles
- sperm use fructose as primary energy source
cells with less polyol pathway ability
(glucose-sorbitol-fructose)
Have less sorbitol dehydrogenase:
- retina
- renal papilla
- Schwann cells
pH above pKa
no H
- acids neg (eg COO- )
- bases neutral
pH below pKa
H
- acids neutral
- bases positive (eg NH3+)
In fructokinase deficiency - what enzyme compensates to in fructose metabolism
hexokinase
fructose –> fructose 6-phosphate…. glycolysis
defect in lipoic acid results in…
2
- lactic acidosis (PDH def)
- Maple Syrup Urine disease (branced-chain ketoacid DH)
(also alpha-KG DH def)
biologically active form of pantothenic acid
coenzyme A
TCA cycle step that requires B5
oxaloacetate –> citrate
B5 = coenzyme A
CoA important in synthesis of…
Vit A Vit D cholesterol steroids heme A FAs AAs proteins
How is pantothenic acid activated
- actively transported into cell
- ATP dependent phosphorylations –> coA
Niacin dependent steps in TCA cycle
(NADH steps)
isocitrate –> alpha-KG
alpha KG –> succinyl CoA
*requires many cofactors
malate –> oxaloacetate
Pompe disease muscle bx
enlarged lysosomes containing periodic acid-Schiff (PAS) + material
infant w/ cardiomegaly, macroglossia, profound muscular hypotonia
Acid maltase (alpha-glucosidase) deficieny
Pompe
accumulation of glycogen with abnormally short outer chains
debranching enzyme deficiency
Cori disease
GLUT 1
RBCs
BBB
basal glucose transport
GLUT 2
hepatocytes
beta cells of pancreas
renal tubular cells
small intestine
regulation of insulin release
GLUT 3
placenta
neurons
GLUT 4
skeletal muscle
adipocytes
insulin mediated uptake
GLUT 5
spermatocytes
GI tract
fructose transport
riboflavin dependent step in TCA cycle
Coenzyme of succinate dehdrogenase:
succinate –> fumarate
glossitis
cheilitis
corneal neovascularization
ribovlavin (B2) deficiency
liver cells with HIGH concentration of F-2,6-BP will have LOW rate of conversion of…
alanine –> glucose
Increases F6P –> F-2,6P
insulin
inhibition of lactate dehydrogenase would halt glycolysis due to depletion of …
NAD+
what step of glycolysis regenerates NAD+ from NADH
pyruvate–> lactate
“red neurons”
description and timeframe
red neurons: sign of IRREVERSIBLE neuronal injury
12-48 hrs after injury
eiosinophilic cytoplasm
pyknotic nuclei
loss of nissl substance
(will fragment and be phagocytized by macrophages)
Micorosopic/Macroscopic changes in ischemic brain tissue
timeframe, description
12-24 hrs
Micro: red neurons
1-4 days
Micro: necrosis and neutrophils
3-5 days
Micro: macrophages
1-2 wks
Micro: reactive gliosis, vascular proliferation around necrotic area
Macro: liquifactive necrosis - well demarcated soft area (1 wk - 1 month)
> 2 wks
Micro: glial scar
Macro: cystic area surrounded by gliosis (> 1mo)
hepcidin –>
hepcidin–>
decreased ferroportin expression on basolateral surface of enterocytes—>
decreased iron secretion into circulation
MCC of primary hemochromatosis
mt in HFE protein
HFE interacts with transferrin receptor to increase endocytosis of the iron-transferrin complex
this iron is added to the regulatory pool to control
mt= sensing falsley low iron levels
holosytolic
apex
radiates to axila
mitral regurg
best indicator of severity of mitral regurg
presence of S3
best indicator of severity for mitral stenosis
S2 to opening snap interval
shorter worse - ?
thin septate hyphae
(with acute angles)
Aspergillus
Giardia
immune defect
IgA
Sitting up from supine
muscles
- external abd obliques
- rectus abdominus
- hip flexors (mainly iliospsoas)
- -> psoas major/minor
- -> iliacus
superior laryngeal nerve - external branch
(innervation)
cricothyroid muscle
superior laryngeal nerve - internal branch (innervation)
sensory innervation above vocal cords
reccurant laryngeal nerve
innervation
all laryngeal muscles except cricothyroid
sensory innervation below the vocal cords
nerve at risk by superior thyroid artery and vein
exterior branch of superior layrngeal
histo of Reye
- microvesicular steatosis of hepatocytes
- NO inflammation
- cerebral edema
Enzyme in galactose metabolism impaired in secondary lactose intolerance
Beta-galactosidase
Lactose (galactosyl-beta-1,4-glucose) –> Galactose
fates of galactose
G1P –> G6P –> pyruvate
UDP-galactose –> Lactose
e.g. in milk production
where does mannose enter glycolysis
mannose –> mannose-6P –> fructose-6P
where does fructose enter glycolysis
fructose ---- (fructokinase)--> fructose-1P ----(Aldolase B)--> glyceraldehyde (and DHAP) -----(Triokinase)---> glyceraldehyde-3-phosphate ----(Aldolase A or B)--> fructose-1,6-BP
**Enters after regulation by PFK1
mushroom toxin
(amatoxins)
inhibit RNA polymerase II
–> halt mRNA synthesis
Euk RNA polymerase i
ribosomal RNA
Euk RNA polymerase II
messenger RNA
Euk RNA polymerase III
transfer RNA
ricin toxin
from castor oil plant ricinus
inhibits protein syth by cleaving the rRNA component of the 60S subunit
Leptin sites of action
- acuate nuclus of hypothal to:
- INHIBIT prod of NPY
- STIM prod of alpha-MSH
lac operon - produces…
- beta-galactosidase
(lactose –> glucose + galactose) - permease
(increases permeability to lactose)
(an unnecessary one - transacetylase)
lac operon - repressor bound state
absent lactose
lactose binds to and releases repressor
lac operon - state with excess glucose and excess lactose
nothing bound
- repressor unbound due to lactose
- CAP (activator) not bound due to excess glucose –> decreasing activity of adenylate cyclase –> decrease intracellular cAMP
lac operon - control of catabolite activator protein (CAP)
- inhibited by low intracellular cAMP
Pigmented gallstones
- enzyme
- risks
infx of biliary tract –>
release of beta-glucuronidase from injured hepatocytes and bacteria—>
hydrolysis of bilirubin glucuronides—>
increase unconj bilirubin in bile
risks: biliary infx with E coli Ascaris Opisthrchis (liver fluke)
common trigger for hepatic encephalopathy
GI bleeding
increase in ammonia and nitrogen absorption by the gut
cells in brain affected by acute rise in ammoninia
astrocytes
neurons
ammonia toxicity results from depletions of… (in the brain)
(2)
GLUTAMATE
- increased conversion of glutamate –> glutamine by glutamine synthetase in astrocytes (excess glutamine –> astrocyte swelling and dysfx)
ALPHA-KETOGLUTARATE
- NH4 can detoxified to glutamate with alpha-KG via glutamate dehydrogenase –> depletes alpha-KG –> impairs energy metabolism (TCA cyle)
Lynch syndrome
genetics
AD
abnormal nucleotide mismatch repair
cofactor in synthesis of delta-aminolevulinic acid
pyridoxal phosphate
succinyl-CoA + glycine (w/ pyridoxal phosphate)—> ALA
ribosomal subunit fx:
- 23S
in 50s ribosome
- facilitate peptide bond formation (peptidyltransferase)
ribosomal subunit fx
- 16S
in 30s ribosome
- contains sequence complementary to the “Shine Dalgamo” sequence on mRNA
- binding of these complementary sequences necessary for initiation of protein translation
Shine Dalgamo sequence
in all prokaryotic mRNA
- located ~10bp up from the AUG start codon
- allow for binding to 16S subunit on 30S ribosome
ApoA-1
LCAT activation (cholesterol esterification)
ApoB-48
chylomicron assembly and secretion by the instestine
ApoB-100
LDL particle uptake by extrahepatic cells
ApoC-II
lipoprotein lipase activation
ApoE-3 and 4
VLDL and chylomicron remnant uptake by liver cells
Kozak consensus sequence
Eukaryotic mRNA
upstream from AUG (methione start)
initiator for translation (i.e. mRNA binding to ribosomes)
- a purine (G or A) positioned 3 bases upstream from the AUG appears to be a key factor
- mt a/w thalassemia intermedia
Beta thalasemia mt causes…
defective transcription, processing, and translation of beta-globin mRNA
Target cell ddx
“THAL” (or “HALT”
- Thallasemia
- HbC disease
- Asplenia
- Liver disease
HbC and HbS electrophoresis
HbC will not travel as far as either normal or HbS;
HbS will not travel as far as normal
HbS
neg charged glutamate –> nonpolar valine (decreased neg charge)
HbS
neg charged glutamate –> positively charged lysine (even less neg charge)
cyanide poisoning antitode mech
Nitrites:
hemoglobin (Fe2+)–> methemoglobin (Fe3+)
methemoglobin binds CN more tightly –> keeps it sequestered in blood and away from mitochondrial enzymes
activators of ALA synthase
Etoh
Barbiturates (think of w/anxiety)
Hypoxia
Repressors of ALA synthase
heme
glucose
Acute Intermittent Porphyria
symptoms
5 P's: Painful abdomen Port wine urine Polyneuropathy Psychological disturbances Precipitated by drugs*
Barbituates Seizure drugs Rifampin Metoclopromide Etoh griseofulvin phenytoin
(also stavation)
Acute intermittent porphyria tx
heme and glucose –> block ALA synthase
Enzyme- acute intermittent porphyria
Porphobilinogen deaminase
Enzyme - porphyria cutanea tarda
uroporphyrinogen decarboxylase
Enzyme - lead poisoning
ALA dehydratase
Ferrochelatase
triggers for sickle cell aggregation
hypoxia
low pH
high 2,3DPG
heme –> biliverdin
enzyme
Heme oxygenase
glutamate residue carboxylation in liver
vitamin
K
essential for some clotting factor production
Active or passive:
1) liver uptake of unconj bili
2) liver excretion of conj bili
1) passive uptake
2) active secretion into bile canniculi*
passive diffusion via baolateral OATP allows conj bili to leak into blood stream
Crigler Najal
enzyme
UDP-glucuronyl transferase
- absent
(conjugation of bili)
Gilbert syndrome
enzyme
UDP-glucuronyl transferase
- low
(conj of bili)
Defect in secretion of bile
Dubin- Johnson
Rotor
Stop codons
UGA
UAA
UAG
“U Go Away”
“U Are Away”
“U Are Gone”
spoon nails + dysphagia
Fe deficiency
Anemia:
PO2
% Saturation
O2 content
pO2: normal
sat: normal
O2 content: low
after beginning chemo: hyperphosphatemia hypocalcemia hyperkalemia hyperuricmia
dx and tx
tumor lysis syndrome
tx (prevention):
hydration + hypouricemic agents (allopurinol or rasburicase)
Rasburicase
MOA
recombinant urate oxidase
uric acid –> allantoin (more soluble than uric acid)
chemo –> cardiotoxicity
drug and prevention
Drug:
doxurubicin
daunorubicin
Prevent:
dexrazone
*trastuzumam (herceptin) also causes cardiotoxicity
chemo –> myelosuppression
2
Drug:
methotrexate
Prevent:
leukovorin (folinic acid)
Drug:
5-FU
Prevent:
uridine
chemo –> hemorrhagic cystitis
Drug: cyclophosphamide
Prevent:
mesna
Give dexrazene with ___ to prevent _____
with: doxurubincin/daunorubicin
to prevent:
cardiotxicity
Give leukovorin with ___ to prevent_____
with:
methotrexate
to prevent:
myelosuppression
Give mesna with ___ to prevent ____
with:
cyclophosphamide
to prevent: hemorrhagic cystitis
Give uridine with ____ to prevent ____
with:
5-FU
to prevent:
myelosuppression
- exertional dyspnea
- pneumonia (–> life threatening acute chest syndrome)
- recurrent abdominal and bone pain
Sickle cell
glutamic acid –> valine
G6PD action
GDPD –> 6-phosphogluconate
*rate limiting step in HMG/pentose phosphate shunt
G6PD deficiency genetics
X-linked
G6PD necessary for:
HMP (pentose phosphate) shunt:
- produce NADPH
- produce ribulose-5-phosphate
mt in JAK2
3 blood d/o
-essential thrombocytosis
(hemorrhagic and thrombotic symptoms)
-polycythemia vera
(pruritis, splenomegaly, thrombotic cx)
- primary myelofibrosis
(severe fatigue, splenomegaly often causing early satiety, hepatomegaly, anemia, bone marrow fibrosis)
Primary myelofibrosis smear
teardrop (dacrocytes)
nucleated RBCs
bisphosphoglycerate mutase
1,3BPG –> 2,3BPG
*consumes energy that would have otherwise been used to produce energy in the form of ATP
(alternate glycolytic pathway)
pyruvate kinase deficiency
[phosphoenolpyruvate --> pyrvate) def --> hemolytic anemia due to failure of glycolysis
–> splenic hypertrophy due to increased work of removing deformed erythrocytes
Haldane effect
binding of O2 drives release of H+ and CO2 from hemeoglobin
Bohr effect
high CO2 and H+ facilitate O2 unloading from Hb
xeroderma pigmentosum
enzyme; genetics
AR
endonuclease - nucleotide excision repair enzyme
UV-specific endonuclease
Fructose -6P –> ribose
enzymes- 2
transaldolase
transketolase
(non-ox/reversible reactions of the HMP shunt)
*all cells
radiation (tx) mech
1) DNA double strand breaks
2) formation of free radicals (reactive oxygen species from ionization of water)
RBCs unable to synth heme b/c of lack of…
mitochondria
necessary for first and final three steps
mTOR pathway
growth factor binds to rec tyrosine kinase
- -> activate phosphoinositide 3-kinase (PI3K)
- -> phospholylates PIP2 to PIP3 (in plasma membrane)
- -> activate protein kinase B (Akt) - a serine/threonin specific kinase
- ->activates mTOR
- ->mTOR translocates to nucleus
- -> induce genes for survival, anti-apoptosis, angiogenesis
*inhibitied by PTEN, a tumor suppressor proetin that removes phosphate from PIP3
Why is HCV genetically unstable
- it’s RNA polymerase lacks proofreading 3’–>5’ exonuclease
- envelope glycoprotein contains a hypervariable region prone to mt
Alkaptonuria
AR
homogentisate oxide def
- step in tyrosine –> fumarate
- dark connective tissue
- brown sclerae
- urine turns black on prolonged exposure to air
may have debilitating arthralgias (homogentisic acid toxic to cartilage)
increased glycogenolysis in muscles (mech)
increased calcium in cytosol
- ->allosterically activates phosphorylase kinase
- -> phosphorylates (activates) muscle phosphorylase
- -> —> glycogen breakdown
additions or deletions of a number of base not in a multiple of 3
framshift
MC cystic fibrosis mt mech
codon deletion of phenylalanine
Antibodies w/ high specificity for rheumatoid arthritis
anti-citrulinated peptide
anti-CCP
main amino acids in elastin
glycine
alanine
valine
(all non-polar)
also contains proline and lysine but most are not hydroxylated (unlike collagen)
what accounts for elastin’s resilance
extensive desmosine crosslinking
(interchain crosslinks involving 4 different lysines on 4 elastin chains)
extracellualar lysyl hydroxylase does crosslinking
severe abdominal pain hypotension hyperventilate met acidosis increased AG high plasma lactate
what enzyme has low activity
pyruvate dehydrogenase
(oxidative phosphorylation pathway)
(this is hypoxia-induced lactic acidosis)
what about the desired gene do you need to know to do pcr
the nucleotide sequence of the regions flanking the target DNA
fibrillin
major component of the microfibrils that form a sheath around elastin fibers
acts as an extracellular scaffold for deposition of elastin extruded from connective tissue cells
abundant in blood vessels, periosteum, and suspensory ligaments of the lens
glycoprotein from viral sythesis that forms spheres and tubules and poorly correlates with viral replication
an envelope component of HBV
(HBsAg)
often made in large excess
location of collagen hydroxylation of proline/lysine
requires vit C
RER
most abundant protein in the human body
collagen
most abundant amino acid in collagen molecule
glycine
at LEAST every 3rd amino acid
defects in ubiquitin-proteasome system can lead to what neurodegen d/os
Parkinson
Alzheimer
PKU tx with tyrosine –> normal serum phenylalanine but elevated PRL
what enzyme is def
Dihydrobiopterin reductase
Tetrahydrobipterin (BH4) cofactor in…
phenylalanine –> tyrosine
tyrosine—>DOPA
synth of serotonin
synth of NO
Alanine –> ?
Aspartate –> ?
via alpha-KG transamination
alanine –> pyruvate
aspartate –> oxaloacetate
cofactor for transamination
B6
major transporter of nitrogen to the liver for disposal
alanine
what carries nitrogen to the kidneys from most tissues
glutamine
glutamine
—(glutaminase)—>
glutamate + NH3
Vit A tox
intracranial htn
skin changes
hepatosplenomegaly
hyperlipidemia
acute:
n/v
vertigo
blurred vision
N-acetylglutamate
- activator of _____ in NH3 exretion
carbomoyl phosphate synthase 1
CO2 + NH3 –> carbomoyl phssphate
entry into the urea cycle
amino group of what aa directly provides N for the urea cycle
aspartate
megoloblastic anemia
neuro abnl
growth retardation
orotic acid in urine
orotic aciduria (AR):
defect in UMP synthase (pyrimidine synth pathway)
unable to convert orotic acid –> UMP
supplement with uridine monophosphate
NB: NORMAL ammonia (vs ornthine transcarbamylase def)
ornithine transcarbamylase def
XR
defect in urea cycle
- increased orotic acid in blood and urine
- HIGH ammonia in blood
- low BUN
- NO megaloblastic anemia
tx: decrease protein phenylbuterate benzoate biotin
enzymes that use B1
pyruvate dehydrogenase
alpha-KG dehydrogenase
transketolase
foamy histiocytes
Niemann-Pick
sphyngomyelin accumulates in histiocytes
metabolism of very long chain fatty acids or fatty acids with branch points at odd numbers
peroxisomes
- VLCFA –> special form of beta ox
- branched chain (e.g. phytanic acid) –> alpha ox
peroxisome defects lead to
neuro deficits from improper CNS myelination
young
spastic paresis of LE and choreoathetoid movements
high arginine
enzyme
arginase
last step in urea cycle
phenylalanine derivatives
phenylalanine —>
–[BH4]–>tyrosine
( also tyrosine—> thyroxine)
–[BH4]–>Dopa
( also Dopa—>Melanin)
- -[B6]-> Dopamine
- -[vit C]-> NE
- -[SAM]-> Epi
Tryptophan derivatives
tryptophan
–[B6]–> Niacin
tyrptophan
- -[B6, BH4]–> serotonin
- –> melatonin
Histadine derivatives
histadine
–[B6]–> histamine
Glycine derivatives
glycine
- -[B6]–> porphyrin
- –> heme
Glutamate dervivatives
glutamate
–[B6]–> GABA
glutamate
—> glutathione
Arginine derivatives
arginine
—> creatine
arginine
—> urea
argininine
–[BH4]–> Nitric Oxide
transamination reaction (vit)
B6
pyridoxal phosphate
met acidosis large AG ketosis hypoglycemia high methylmalonic acid
deficient reaction
Isomerization
methylmalonyl CoA –> Succinyl CoA
(this is methylmalonic acidemia)
what amino acids should be avoided in Maple Syrup Urine Disease
(branched chain)
leucine
isoleucine
valine
principal stabilizing force for secondary structure of proteins
H bonds
cofactors for branched chain alpha-ketoacid dehydrogenases
(like PDH and alpha-KG DH)
TLC For Nobody thiamine lipoic acid coenzyme A FAD NAD
Maple Syrup Urine Disease enzyme
branched chain alpha-ketoacid-dehydrogenase
Propionyl CoA
comes from….
- AAs: Threonine Methionine Valine Isoleucine
- odd-numbered FAs
- cholesterol side chains
