Biochemistry

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Question

Answer

Rate limiting reaction in cholesterol synthesis

HMG Co-reductase

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Findings in PKU

mousy odor; tyrosine missing (must be supplied by diet); can diagnose by amniocentesis and finding abnormal gene; Tx = eliminate Phenylalanine from diet (Nutrasweet is aspartate/phenylalanine...can't use it)

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I cell disease

inability to phosphorylate the mannose residues of potential lysosomal enzymes (they cannot be taken up by lysosomes to degrade complex substrates)

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Number of glucoses necessary to build palmitic acid a 16 carbon compound

4 glucoses (each glucose produces 2 acetyl-CoA which contributes 2 carbons each)

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Insulin lack in DKA

decreased glycolysis, glycogenesis, FA synthesis, storage of fat in adipose

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Uncoupling agents (ex: alcohol and salicylates)

produces brown fat from increased heat from rxns trying to increase the generation of more protons to make ATP

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Von Gierke's disease

dec glu-6-phosphate (gluconeogenic enzyme) w/dec in glucose (fasting hypoglycemia) and inc in glucose 6-phosphate w/production of normal glycogen in liver and kidneys; Stimulation Test = glucagon, fructose, etc cannot inc glucose levels d/t lack of enzyme

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Biochemical processes in both cytosol and mitochondria

urea cycle, heme synthesis, gluconeogenesis

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Female with pheochromocytoma

consider treating with dietary restriction of phenylalanine (essential AA) and tyrosine (not essential)

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Pregnant female with PKU

consider treating with dietary changes: low in phenylalanine, high in tyrosine (avoid nutrasweet)

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Lesch Nyhan

SXR with absent HGPRT (Hypoxanthine guanine phosphoribosyltransferase); self mutilation, hyperuricemia, MR

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Glucokinase

only in liver; high Vm and high Km; not inhibited by glucose-6-phosphate

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Hexokinase

in all tissues; inhibited by glucose-6-phosphate; low Vm and low Km

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Maple syrup urine disease

branched chain amino acids

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Key enzyme in gluconeogenesis

fructose-1,6-bisphosphatase (catalyzes conversion of fructose-1,6-bisphosphate to fructose-6-phosphate)

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Locations of glucose-6-phosphatase

gluconeogenic hormone; liver, kidney, intestinal epithelium (not as much); Absent in von-Gierke's dz

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Carnitine Shuttle

carries even chained fatty acids

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Malate Shuttle

carries NADH

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Functions of LDL

vitamin D synthesis, other steroid synthesis, cell membranes, synthesis of bile salts/acids

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Acetyl CoA uses

FA synthesis, CH synthesis, ketone body synthesis

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Function of urea cycle

eliminates ammonia

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Debrancher deficiency

epinephrine given and only small branched chains are found

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Origin of apolipoprotein 100

liver

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Origin of apolipoprotein 48

intestine

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Rate limiting step in glycogenolysis

glycogen phosphorylase

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Reason why liver cannot use ketones for fuel

cannot activate acetoacetate in mitochondria which requires succinyl CoA; (acetoacetate CoA transferase, a thiotransferase enzyme, is needed to convert AcAc into acetoacetyl CoA

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McArdles disease

abscent muscle phosphorylase; inc glycogen in muscle; no increase in lactic acid after exercise

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Pregnant woman is a beer drinker, what supplements does she need?

folate (EtOH inc loss of folate in urine/stool); she should probably stop drinking to prevent FAS (iron is NOT affected)

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Insulin

key hormone in fed state

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Glucagon

key hormone in fasting state

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Mannose-6-phophate

involved in transfer of dolichol (lipid) in RER in the synthesis of O-linked glycosides

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Major source of NADPH

HMP shunt; malate dehydrogenase rxn to a lesser extent; (it supplies reducing equivalents)

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Mutation changes an amino acid sequence, which one would have the greatest effect on migration in a serum ptn electrophoresis?

one with the most negative charge (most acidic): GLUTAMINE; (the one that would remain closest to the anode (- pole) is the most basic: ARGININE)

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Mechanism of ketoacidosis in DKA

inc b-oxidation of FAs and production of acetyl-CoA, which is used up by the liver to synthesize ketone bodies

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Promoter location

on a linear gene drawing with labels, pick the upstream location

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Energy source for protein synthesis

GTP

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Isoenzyme with 2 genes, 4 subunits

LDH isoenzymes; 5 isotypes (LLLL, LLLH, LLHH, LHHH, HHHH)

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Second messengers

atrial natriuretic peptide: cGMP; Insulin: tyrosine kinase, Nicotinic: ion channels

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Best method for detecting relatedness of a new bacteria

restriction fragment length polymorphism

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Mutations: silent, missense, nonsense

no change in AA, new AA, early stop codon

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Frameshift mutation

truncated protein

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Primase on lagging strand

(single origin of replication w/discontinuous Okazaki fragments) makes RNA primer on which DNA polymerase III can initiate replication (prokaryotic)

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DNA polymerase III (prokaryotic)

5' --> 3' synthesis and proofreads with 3' --> 5' exonuclease

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DNA polymerase I (prokaryotic)

excises RNA primer with 5' --> 3' exonuclease

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DNA topoisomerases (prokaryotic)

create nick in helix to relieve supercoils

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RNA polymerase I, II, III (eukaryotes only)

rRNA (most abundant), mRNA (biggest), tRNA (smallest)

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Start and Stop codons

AUG (methionine (euk) or f-methionine (pro)); UGA (you go away), UAA (you are away), UAG (you are gone)

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Promoter region vs. enhancer

upstream site (from gene locus) for RNA polymerase/transcription factor binding; versus any location before or within a gene for transcription factors to bind and alter expression

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Introns vs. exons

introns stay in the nucleus, wheras exons exit and are expressed

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DNA synthesis can be prevented by nucleoside analogs such as:

Cytosine arabinoside, Zidovudine, and Acyclovir (they are useful in antiviral and anticancer therapy)

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Streptomycin

binds to 30S subunit and distorts its structure, interfering with the initiation of protein synthesis

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Tetracyclines

interact with small ribosomal subunits, blocking access of the aminoacyl-tRNA to the mRNA-ribosome complex

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Puromycin

has structural resemblance to aminoacyl-tRNA and becomes incorporated into the growing peptide chain, causing inhibition of further elongation in both prokaryotes and eukaryotes; acts at "peptidyl-transferase" step

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Chloramphenicol

inhibits prokaryotic "peptidyltransferase." high levels may also inhibit mitochondrial protein synthesis

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Clindamycin and Erythromycin

bind irreversibly to a site on teh 50S subunit of the bacterial ribosome, thus inhibiting translocation

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Diphtheria Toxin

inactivates the eukaryotic elongation factor, eEF-2, thus preventing translocation in the ribosome

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Regulation of RNA synthesis

Eukaryotes (methylation, amplification, rearrangement); Prokaryotes (operons w/promoter, operator & repressor: inducable lac operon, repressible tryptophan operaon, positive control arabinose operon, catabolite repressor lac operaon if glucose is present)

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Disulfide bonds

play major role in maintaining tertiary structure of proteins

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Peptidoglycan cross-linking in bacterial cell wall

disrupted by penicillin and cephalosporins

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Blots = Snow Drop

Southern = DNA, Northern = RNA, Western = Protein

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ELISA

tests antibody-antigen reactivity; determines if pt's blood contains either an Ab or Ag of interest; color change occurs if present

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Autosomal dominant

usu defect in structural gene; often pleiotropic; many generations; male and female affected; presents after puberty; family Hx crucial for Dx

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Autosomal recessive

usu enzyme deficiencies; 25% of offspring affected usu seen ONLY in 1 generation; more severe than dominant; presents in CHILDHOOD

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X-linked recessive

sons of hetero moms have 50% chance; NO MALE TO MALE transmission; more severe in males; hetero females possible

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X-linked dominant

d/t either parent; All female offspring of father affected; ex: hypophosphatemic rickets; every generation affected

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Mitochondrial inheritance

transmitted only thru mom; all offspring of affected females may show signs of dz; ex: Leber's hereditary optic neuropathy; mitochondrial myopathies

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Anticipation of genetic trait

severity of dz worsens w/age or onset of dz is earlier in succeeding generations (ex: Huntington's)

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Loss of genetic heterozygosity

ex: both alleles of a tumor suppressor gene must be mutated for cancer to develop (this is not the case for oncogenes)

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Dominant negative mutation

exertion of a dominant effect; a heterozygote produces a nonfxnl altered ptn that also prevents the normal gene product from functioning

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Hardy-Weinberg Law Assumptions for Population Genetics: p2 + 2pq + q2 = 1; p + q = 1 (2pq = heterozygote prevalence)

1. there is no mutation occuring at the locus; 2. there is no selection for any of the genotypes at the locus; 3. mating is completely random; 4. there is no migration into or out of the population

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Fabry's lysosomal storage dz

XR; a-galactosidase A deficiency (accumulation of ceramide trihexoside); peripheral neuropathy, angiokeratomas, CV and renal dz;

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Hunter's lysosomal storage syndrome

XR; Iduronate sulfatase deficiency (accumulation of heparan sulfate, dermatan sulfate); mild hurler's + AGGRESSIVE behavior, NO corneal clouding

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Hurler's lysosomal storage syndrome

AR; a-L-iduronidase deficiency (accumulation of hepara and dermatan sulfate); DD, GARGOYLISM, airway obstruction, CORNEAL clouding, hepatosplenomegaly

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Metachromic Leukodystrophy lysosomal storage dz

AR; arylsulfatase A deficiency (accumulation of cerebroside sulfate); central and peripheral DEMYELINATION w/ataxia and dementia

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Krabbe's lysosomal storage dz

AR; b-galactosidase deficiency (accumulation of galactocerebroside); peripheral neuropathy, DD, optic atrophy

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Tay-Sach's lysosomal storage dz

AR; hexosaminidase A deficiency (accumulation of GM2 ganglioside); progressive neurodegeneration, DD, CHERRY-RED SPOT, lysozymes with ONION SKIN

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Niemann-Pick lysosomal storage dz

AR; sphingomyelinase deficiency (accumulation of sphingomyelin); progressive neurodegeneration, heatosplenomegaly, CHERRY-RED SPOT on MACULA

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Gaucher's lysosomal storage dz

AR; b-glucocerebrosidase deficiency (accumulation of glucocerebroside); hepatosplenomegaly, aseptic necrosis of femur, BONE CRISIS, Gaucher's cells (MQs)

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Cell cycle

Mitosis is shortest (prophase, metaphase, anaphase, telophase); G1 and Go are variable, but rapidly dividing cells have shorter G1

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Competitive inhibition

resembles substrate; no change in Vmax; inc Km (lower affinity for substrate)

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Noncompetitive inhibition

dec in Vmax; no change in Km

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Phosphatidylcholine

aka lecithin; component of RBC membranes, myelin, bile and SURFACTANT; also used in esterification of cholesterol

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Ouabain

inhibits binding to K site of Na-K-ATPase

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Cardiac glycosides (digoxin, digitoxin)

inhibit Na-K-ATPase causing increased cardiac contractility

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Na-K-ATPase pump

ATP site on cytoplasmic side, for each ATP consumed, 3 Na go out and 2 K come in; during cycle pump is phosphorylated

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alpha1 receptor

q G-ptn class; inc vascular smooth muscle contraction

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alpha 2 receptor

i G-ptn class; dec sympathetic outflow; dec insulin release

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beta1 receptor

s G-ptn class; inc HR, inc contractility, inc renin release, inc lipolysis, inc aqueous humor formation

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beta2 receptor

s G-ptn class; vasodilation, bronchodilation, inc glucagon release

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M1 receptor

q G-ptn class; CNS fxn

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M2 receptor

i G-ptn class; dec HR

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M3 receptor

q G-ptn class; inc exocrine gland secretions

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D1 receptor

s G-ptn class; relaxes renal vascular smooth muscle

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D2 receptor

i G-ptn class; modulates transmitter release, esp in brain

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H1 receptor

q G-ptn class; inc nasal and bronchial mucus production, contraction of bronchioles, pruritis, pain

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H2 receptor

s G-ptn class; inc gastric acid secretions

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V1 receptor

q G-ptn class; inc vascular smooth muscle contraction

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V2 receptor

s G-ptn class; inc H20 permeability and reabsorption in collecting tubules of kidney

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q G-ptn class (a1, M1, M3, H1, V1)

Phospholipase C --> converts lipids to PIP2 --> IP3 and DAG --> inc [Ca]in and PKC

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s G-ptn class (b1, b2, D1, H2, V2)

Adenylcyclase --> converts ATP to cAMP --> PKA

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i G-ptn class (a2, M2, D2)

Adenylcyclase --> dec cAMP --> dec PKA

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Collagen types

I (90%; bone, tendon, skin, fascia, dentin, cornea, late wound repair); II (cartilage, vitreous, nucleus pulposus); III (reticulin; skin, vessels, uterus, fetal, granulation tissue); IV (basment membrane); X (epiphyseal plate)

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Ehlers-Danlos Syndrome

faulty collagen synthesis; hyperextensible skin and joints, bleeding/bruising; a/w berry aneurysms and variable inheritance patterns

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Osteogenesis imperfecta

AD; abnml collagen synthesis; multiple fxs, blue sclera; type II is fatal in utero/neonatal period

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ATP

aerobic metabolism (38 via malate shuttle; 36 via G3P shuttle); Anaerobic glycolysis (produces 2 ATP/glucose)

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SAM (s-adenosyl-methionine) - the methyl donor of man

transfers methyl units to acceptors in synth of phosphocreatine (a high-energy phosphate active in muscle ATP production); regeneration dependent on B12

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ATP is precursor

cAMP via adenylate cyclase

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GTP is precursor

cGMP via guanylate cyclase

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Glutamate is precursor

GABA via glutamate decarboxylase (needs B6)

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Choline is precursor

ACh via choline acetyltransferase (ChAT)

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Arachidonate is precursor

prostaglandins, thromboxanes, leukotrienes via COX/lipoxygenase

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Fructose-6-P is precursor

fructose-1,6-bisphosphate via PFK, the rate limiting enzyme of glycolysis

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1,3-BPG is precursor

2,3-BPG via bisphosphoglycerate mutase

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NADPH uses as electron donor

anabolic processes, respiratory burst (release of reactive oxygen species), P-450

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Hexokinase vs Glucokinase

Glucokinase is only in liver (lower affinity (hi Km), but higher capacity (hi Vmax)); Hexokinase is feedback inhibited by G6P (throughout body)

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Irreversible enzymes in glycolysis

hexokinase/glucokinase (glu-->G6P); PFK (rate-limiting; F6P-->F1,6-BP); Pyruvate Kinase (PEP-->Pyruvate); Pyruvate DH (Pyruvate-->Acetyl-CoA)

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Hexokinase/glucokinase regulation

inhibited by G6P

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Regulation of PFK

Inhibited by ATP, Citrate; Activated by: AMP and F-2,6-BP

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Regulation of Pyruvate Kinase

Inhibited by: ATP and Alanine; Activated by: F-1,6-BP

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Regulation of Pyruvate DH

Inhibited by: ATP, NADH, Acetyl-CoA

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Enzyme deficiencies a/w hemolytic anemia (b/c RBCs depend solely on glycolysis since they lack mitochondria)

hexokinase, glucose phosphate isomerase, aldolase, triosephosphate isomerase, phosphate glycerate kinase, enolase, pyruvate kinase

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Pyruvate DH complex (similar to a-ketoglutarate DH complex)

cofactors: 1st 4 B vitamins + Lipoic Acid (Thiamine/TPP, FAD, NAD, Pantothene-->CoA, Lipoic Acid); activated by exercise which inc NADH, ADP and Ca

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Pyruvate DH deficiency

causes lactic acidosis and neurologic defects (esp alcoholics w/B1 deficiency); Tx = intake of ketogenic nutrients (high fat; Lysine and Leucine)

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What is needed to generate glucose from pyruvate?

6 ATP equivalents

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What carries amino groups from muscle to liver?

Alanine

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What can be used to replenish TCA cycle or in Gluconeogenesis?

Oxaloacetate

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Cori cycle

transfers excess reducing equivalents from RBCs and muscle to liver, allowing muscle to fxn anaerobically, netting 2 ATP

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TCA Cycle - how many ATP are produced/Acetyl-CoA and per Glucose

12 ATP/Acetyl-CoA (3 NADH, 1 FADH2, 2 CO2, 1 GTP); 24 ATP/glucose (b/c glu = 2 pyruvates)

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Intermediates in TCA Cycle: Cindy is Kinky So She Fornicates More Often

Citrate, Isocitrate, a-Ketoclutarate, Succinyl-CoA, Succinate, Fumarate, Malate, Oxaloacetate

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1 NADH equals? 1 FADH2 equals?

3 ATP; 2ATP

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Electron transport inhibitors

Directly inhibit electron transport, causing dec of proton gradient and block of ATP synthesis: rotenone, antimycin A, CN-, CO (

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ATPase Inhibitor

oligomycin; direct inhibition; increases proton gradient, but no ATP is produced d/t hault of electron transport

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Uncoupling agents

2,4-DNP; increases permeability of membrane, dec proton gradient and inc O2 consumption; ATP synthesis stops, Electron transport continues

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Irreversible enzyems in Gluconeogenesis (liver, kidney, intestine; NOT muscle)

"Pathway Produces Fresh Glucose" = Pyruvate carboxylase, PEP carboxykinase, F-1,6-BP, G6Pase; deficiency of any can cause hypoglycemia (ex: G6Pase = von Gierke's dz)

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Pyruvate carboxylase

located in mitochondria; Pyruvate --> Oxaloacetate; Requires Biotin, ATP; Activated by Acetyl-CoA

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PEP Carboxykinase

located in cytosol; OAA --> PEP; requires GTP

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F-1,6-BPase

located in cytosol; F-1,6-BP --> F6P

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G6Pase

located in cytosol; G6P --> glucose;

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Pentose Phosphate Pathway (HMP shunt)

located anywhere FA or steroid synthesis occurs; Produces ribose-5-P from G6P for nucleotide synthesis AND NADPH from NADP+ for FA/Steroid biosynthesis (and maintaining reduced glutathione in RBCs)

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G6P DH deficiency (rate limiting step in PPP pathway/HMP (hexose monophosphate) shunt)

XR; lack of NADPH = inability to reduce glutathione = inability to detoxify free radicals = HEMOLYTIC ANEMIA; more commonly in blacks; Forms Heinze bodies (altered Hb precipitates in RBCs); a/w FAVA beans, sulfonamides, primaquine and anti-TB drugs

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Fructose Intolerance d/t deficiency of Aldolase B

AR; hypoglycemia, jaundice, cirrhosis d/t: accumulation of fructose-1-phosphate causes dec in available phosphate = inhibition of glycogenolysis and gluconeogenesis; Tx = reduce fructose/sucrose intake

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Galactosemia d/t absence of Galactose-1-phosphate uridyltransferase

AR; cataracts, hepatosplenomegaly, MR d/t: accumulation of toxins (galactitol); Tx = exclude galatose and lactose from diet

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Lactase deficiency

age-dependent or hereditary intolerance (Asians/Blacks); bloating, cramping, osmotic diarrhea; Tx = avoid milk or add lactase pills

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Essential AAs: PriVaTe TIM HALL

Ketogenic (Leu, Lys), Glucogenic/Ketogenic (Ile, Phe, Trp), Glucogenic (Met, Thr, Val, Arg, His); arg/his - required for growth

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Basic amino acids

Arg and Lys; positively charged, found in high amounts in histones b/c they bind negatively charged DNA

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Ammonium transport btw liver and muscle

Alanine and Glutamine

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Urea Cycle

degrades AA to amino grps (makes up 90% of nitrogen in urine); occurs in LIVER; Carbamoyl Phosphate incorporation is the only mitochondrial step (others occur in cytosol)

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Urea Cycle Intermediates: Ordinarily, Careless Crappers Are Also Frivolous About Urination

Ornithine, Carbamoyl phosphate, Citrulline, Aspartate, Agrininosucinate, Fumarate, Arginine Urea

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Phenylalanine Derivatives

tyrosine, thyroxine, dopa, dopamine, NE, Epi, Melanin

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Tryptophan Derivatives

Niacin (NAD+/NADP+), Serotonin, Melatonin

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Hisidine Derivatives

Histamine

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Glycine Derivatives

Porphyrin, Heme

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Arginine Derivatives

Creatine, Urea, Nitric Oxide

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Phenylketonuria

AR; can't convert Phe to tyrosine d/t lo phenylalanine hydroxylase or cofactor; Tyrosine becomes essential and Phe adds up (excess phenylketones); MR, growth retardation, fair skin, eczema, musty odor; Tx = dec Phe (in nutrasweet), inc Tyrosine

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Alkaptonuria

deficiency of homogentisic acid oxidase (degradative pathway for tyrosine); Alkapton bodies turn standing urine and CT black; Benign dz, may have arthralgias

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Albinism

Deficiency of either Tyrosinase (no melanin synth) OR Defective Tyrosine Transporters (dec amts of melanin); Can be d/t lack of neural crest migration; Inc risk of skin cancer

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Homocystinuria

Defective Cystathione Synthase or Methionine Synthase; Cysteine becomes essential for diet (or inc B6); MR, osteoporosis, tall staure, kyphosis, lens subluxation

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Cystinuria

common defect in tubular AA transporter for COLA (cystine, ornithine, lysine, arginine); Can case cystine kidney stones; Tx = acetazolamide to alkalinize the urine

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Maple Syrup Urine Dz

blocked degeneration of branched AA (Ile, Leu, Val = "I love vermont" maple syrup) d/t dec a-ketoacid DH; Inc a-ketoacids in blood cause CNS defects, MR, death;

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Adenosine Deaminase Deficiency

Purine salvage deficiency; can cause SCID (T and B cell immunodeficiency - bubble boy); Excess ATP and dATP inhibits ribonucleotide reductase; Prevents DNA synthesis and dec lymphocyte count; 1st dz treated by gene therapy

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Lesch-Nyham Syndrome

XR; LNS - lacks nucleotide salvage (purine) d/t absence of HGPRTase (converts hypoxanthine to IMP and Guanine to GMP); MR, self-mutilation, aggression, gout, choreoathetosis, hyperuricemia

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FA degradation occurs

where its products will be consumed (in mitochondria); transported into mito via carnitine shuttle (inhibited by cytoplasmic malonyl-CoA)

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FA synthesis occurs

in cytosol; transported via citrate shuttle

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Liver: Fed vs Fasting State

In PHasting state, PHosphorylate

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Type I Glycogen Storage Dz: Von Gierke's

G6Pase deficiency; liver becomes a muscle; severe fasting hypoglycemia; very high glycogen storage in liver

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Type II Glycogen Storage Dz: Pompe's

Pompe's trashes the Pump (heart, liver, muscle); lysosomal a-1,4-glucosidase def; Cardiomegaly and systemic probs leading to death

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Type III Glycogen Storage Dz: Cori's

Deficiency of debranching enzyme a-1,6-glucosidase

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Type IV Glycogen Storage Dz: McArdle's

McArdle's: Muscle; skeletal muscle glycogen phosphorylase deficiency; inc glycogen in muscle but cannot break it down; cramps, myoglobinuria w/strenuous exercise

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Glycogen Storage Diseases: Very Poor Carbohydrate Metabolism

Von Gierke's, Pompe's, Cori's, McArdle's

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Ketone Bodies

FA and AA (in liver) ==> acetoacetate + b-hydroxybutryate (used in muscle/brain); found in urine (from HMG-CoA) d/t starvation and DKA; brain makes 2 Acetyl-CoAs from them; fruity breath d/t actone

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Insulin is not necessary to moves glucose into most cells: BRICK L

Brain, RBCs, intestine, cornea, kidney, liver

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Insulin

needed for uptake by adipose and skeletal muscle uptake (GLUT4 transporters); GLUT2 receptors are on beta cells of pancreas; it inhibits glucagon release by alpha cells; serum C-peptide isn't present w/exogenous insulin shots

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Anabolic effects of insulin

inc glucose transport, inc glycogen storage/synthesis, inc TG synthesis/storage, inc Na retention (kidneys), inc ptn synthesis (muscles); phosphorylation (versus dephosphorylation with glucagon)

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Cholesterol synthesis

rate-limiting step catalyzed by HMG-CoA reductase (conversion of HMG-CoA to mevalonate); 2/3 esterified by LCAT; INIHIBITED by: Lovastatin

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Lipoprotein Lipase

FA uptake into cells from chylomicrons and VLDLs

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Hormone sensitive lipase

degradation of stored TGs

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Major Apolipotroteins

A-I (activates LCAT), B-100 (Binds LDL receptor); C-II (Cofactor for lipoprotein lipase); E (mediates Extra (remnant uptake)

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Chylomicrons (B, A, C, E)

from intestinal epithelium; delivers dietary TGs to tissues and cholesterol to liver; excess = pancreatitis, lipemia, retinalis, eruptive xanthomas

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VLDL (B, C, E)

from liver; delivers hepatic TGs to tissues; excess = pancreatitis

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LDL (B100 mediates binding to cell surface for endocytosis)

delivers hepatic cholesterol to tissues; formed by lipoprotein lipase modification of VLDL in periphery; taken up by target tissues via endocytosis; Excess = xanthomas, atherosclerosis, arcus corneae

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IDL

formed from degradation of VLDL; delivers TG and cholesterol to Liver to be degraded to LDL

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HDL (A activates LCAT for cholesterol esterification; CEPT - transfers CE esters to other lipoptn particles)

mediates centripital transport of cholesterol (reverse; from periphery to liver); a repository for apoC and apoE (needed for chylomicron and VLDL metabolism); secreted by LIVER and INTESTINE

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LDL and HDL carry the most cholesterol, just in different directions

HDL is healthy (periphery to liver); LDL is lousy (liver to periphery)

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Familial Dyslipidemia Type I: Hyperchylomicronemia

inc chylomicrons; elevated TGs d/t lipoprotein lipase deficiency or altered apoC-II

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Familial Dyslipidemia Type IIa: Hypercholesterolemia

inc LDL, inc cholesterol d/t dec in LDL receptors

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Familial Dyslipidemia Type IIb: Combined Hyperlipidemia

inc LDL, VLDL; inc TG and cholesterol; d/t inc hepatic synthesis of VLDL

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Familial Dyslipidemia Type III: Dysbetalipoproteinemia

inc IDL, VLDL; inc TG and cholesterol; d/t altered apoE

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Familial Dyslipidemia Type IV: Hypertriglyceridemia

inc VLDL; inc TG; d/t hepatic overproduction of VLDL

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Familial Dyslipidemia Type V: Mixed Hypertriglyceridemia

inc VLDL and chylomicrons; inc TG and cholesterol; d/t inc production and dec clearance of VLDL and chylomicrons

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Which metabolic processes occur in the Mitochondria?

FA oxidation (b-oxidation), Acetyl-CoA Production, Krebs Cycle

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Which metabolic processes occur in the Cytosol?

Glycolysis, FA synthesis, HMP shuttle, Protein Synthesis (RER), Steroid Synthesis (SER)

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Which metabolic processes occur in both mitochondria and cytosol?

Gluconeogenesis, Urea Cycle, Heme Synthesis

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Porphyria Symptoms: 5 Ps

Painful abdomen, pink urine, polyneuropathy, psychological disturbances, precipitated by drugs

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Lead Poisoning Porphyria

inhibits ferrochelatase and ALA dehydrase; Coproporphyrin and ALA accumulate in urine

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Acute Intermittant Porphyria

Deficiency in uroporphyrinogen I synthetase; Porphobilinogen and delta-ALA accumulate in urine

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Porphyria Cutanea Tarda

Deficiency in uroporphyrinogen decarboxylase; uroporphyrin accumulates in urine (tea-colored) w/photosensitivity

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Underproduction of heme produces

microcytic hypochromic anemia

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Heme catabolism (scavenged from RBC and Fe2+ is reused)

Heme --> biliverdin --> bilirubin (CNS toxic, albumin transport to liver). Liver conjugates bilirubin with glucuronate (excreted in bile); Urobilinogen (intestine intermediate) and Urobilin (excreted in urine)

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TCA cycle

regulated by Citrate Synthase; Inhibited by ATP and long chain acyl-CoA; Need for ATP drives cycle with supply of NAD+

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Glycolysis and Pyruvate Oxidation

Regulatory enzymes (Phospofructokinase-1, Pyruvate DH); Activators (AMP, F2,6-BP in liver, F1,6-BP in muscle; CoA, NAD, ADP, pyruvate); Induced by Insulin/inhibited by glucagon; regulates TCA

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Inhibitors of Glycolysis/Pyruvate Oxidation

Citrate (FAs, ketone bodies), ATP, cAMP; Acetyl-CoA, NADH, ATP (FAs, ketone bodies); Glucagon

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Gluconeogenesis

Enzymes (Pyruvate carboxylase, PEP carboxykinase, F1,6-BPase); Activators (acetyl-CoA, cAMP, glucagon, glucocorticoids), Inhibitors (ADP, AMP, F2,6-BP, insulin)

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Glycogenesis

Major enzyme (Glycogen Synthase); Activators (Insulin); Inhibitor (phosphorylase (liver); cAMP, Ca (muscle), glucagon, epinephrine)

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Glycogenolysis

Major enzyme (phosphorylase), Activators (cAMP, Ca (muscle), glucagon (liver), epinephrine); Inhibitors (insulin)

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Pentose phosphate pathway

Major enzyme (G6P DH); Activators (NADP+, Insulin); Inhibitor (NADPH)

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Lipogenesis

Major enzyme (Acetyl-CoA carboxylase); Activators (Citrate, Insulin); Inhibitors (long-chain acyl-CoA, cAMP, glucagon (liver))

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Cholesterol Synthesis

Major enzyme (HMG-CoA reductase); Activator (Insulin); Inhibitor (cholesterol, cAMP, glucagon (liver), drugs (lovastatin))

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Hb Structure Regulation (T (taut) versus R (relaxed) forms)

inc Cl, H, CO2, DPG and temp = favors T form and O2 unloading (lower affinity in T form)

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Methemoglobinemia

oxidized form of hemoglobin (Ferric, Fe3+) that does not bind O2 as readily as reduced Ferrous (Fe2+) form

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CO2 transport in blood

binds to AA in globin chain, not to heme; binding favors T form which promotes O2 unloading; must be transported from tissues to lungs usu in form of bicarb in plasma

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Fat soluble vitamins (A vision, D bone/Ca homeostasis, K clotting, E antioxidant)

absorption depends on ileum and pancreas, toxicity d/t accumulation in fat; deficiency common from malabsorption (cystic fibrosis, sprue, mineral oil, steatorrhea)

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Vitamin B complex deficiencies

a/w dermatitis, glossitis, diarrhea; B12 is the only one that is stored in body (liver)

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Vitamin A (retinol) function

constituent of visual pigments

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Vitamin A deficiency and Excess

Night blindness, dry skin, impaired immune response VERSUS Arthralgias, fatigue, HAs, skin changes, sore throat, alopecia

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Vitamin B1 (thiamine) function

TPP is cofactor for oxidative decarboxylation of a-keto acids (pyruvate/a-ketoglutarate) and for transketolase in HMP shunt

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Vitamin B1 (thiamine) deficiency

Wernicke-Korsakoff and Ber1-Ber1 (polyneuritis, cardiac pathology, edema; wet = dilated cardiomyopathy)

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Vitamin B2 (riboflavin) function

cofactor in oxidation and reduction (FADH2); FAD and FMN are derived from riboFlavin (B2 = 2 ATP)

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Vitamin B2 (riboflavin) Deficiency

the 2 Cs; cheliosis, corneal vascularization, and angular stomatitis

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Vitamin B3 (niacin) Function

part of NAD+ and NADP+ (used in redox rxns); derived from tryptophan; (B3 = 3ATP)

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Vitamin B2 (niacin) Deficiency

Pellagra (3 Ds: diarrhea, dementia, dermatitis and beefy glossitis); can be caused by Hartnup dz, malignant carcinoid, and INH

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Vitamin B5 (pantothenate) Function

Pantothen-A is in Co-A; part of FA synthase; cofactor for acyl transfers

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Vitamin B5 (pantothenate) Deficiency

Dermatitis, enteritis, alopecia, adrenal inusfficiency

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Vitamin B6 (pyridoxine) function

Pyridoxal phosphate (PP) a cofactor in transmamination (ex: AST/ALT), decarboxylation and trans-sulfuration

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Vitamin B6 (pyridoxine) Deficiency

Convulsions, hyperirritability, (deficiency inducible by INH and OCPs)

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Biotin Function

Cofactor for carboxylations (Pyruvate --> OAA; Acetyl-CoA --> Malonyl-CoA; Proprionyl CoA --> Methylmalonyl-CoA)

🗑

Biotin Deficiency

Dermatitis, enteritis; caused by Abx and ingestion of raw eggs; "AVIDin in egg whites AVIDly binds Biotin"

🗑

Folic Acid Function

Coenzyme for 1-carbon transfer; involved in methylation; important for synthesis of nitrogenous bases in DNA and RNA

🗑

Folic Acid Deficiency

**mc vitamin deficiency in US; macrocytic megaloblastic aneima (no neurologic symptoms like B12 def); sprue; Tx = eat green veggies, not stored well; prevention of neural tube defects; PABA is precursor in bacteria; Sulfa drugs and Dapsone are PABA analog

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Vitamin B12 (cobalamin) Function

cofactor for homocysteine methylation and methylmalonyl-CoA handling; stored in liver, made only by microbes; found only in animal products

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Vitamin B12 (cobalamin) Deficiency

Macrocytic, megaloblastic anemia; NEURO symptoms (optic neuropahty, parasthesias), glossitis; d/t malabsorption (sprue, enteritis, Diphyllobothrium latum), pernicious anemia (no intrinsic factor), Crohn's dz (no terminal ileum); Detected by Schilling Test

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Vitamin C (ascorbic acid) Function

Cross-links collagen; facilitates Fe absorption (maintains Fe2+ reduced form), cofactor for dopamine --> NE conversion

🗑

Vitamin C (ascorbic Acid) deficiency

Scruvy; sailors

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Vitamin D Function

inc intestinal absorption of Ca and Phosphate; good for bones; D2 = ergocalciferol (milk); D3 = cholecalciferol (sun-exposed skin); 25-OH D3 = storage form; 1,25(OH)2 D3 = active form

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Vitamin D Deficiency

Rickets in kids (bending); Osteomalacia in adults (soft bones), hypocalcemic tetany

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Vitamin D Excess

Hypercalcemia, loss of appetitie, stupor; a/w Sarcoidosis (epithelioid MQs convert Vit D to active form)

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Vitamin E Function and Deficiency

Antioxidant needed for Erythrocytes; Deficiency = increased fragility of RBCs

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Vitamin K Function

necessary for carboxylation of glutamate residues on coagulation and clotting ptns (X, IX, II, VII, C and S)

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Vitamin K Deficiency

neonatal hemorrhage w/inc PT and PTT, but normal bleeding time; can occur after broad spectrum Abx (b/c of death of intestinal flora); antagonized by Warfarin

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Alcohol Metabolism

NAD+ is limiting reagent; Disulfiram (inhibits acetaldehyde DH; this is a prevention drug so if pt drinks they begin to feel hung over from accumulation of acetaldehyde)

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Ethanol hypoglycemia

metabolism increases NADH/NAD+ ratio in liver; pyruvate is converted to latate and OAA to malate; this inhibits gluconeogenesis and causes hypoglycemia; it also causes hepatic fatty change (steatosis) in chonic alcoholics d/t shunting away from glycolysis

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Kwashiorkor

protein malnutrition; skin lesions, edema, liver malfxn (fatty change); little red johnny

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Marasmus

protein-calorie malnutrition; tissue wasting

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