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beta glycosidic bond
btw C'1 of sugar and N9 of purine/N1 of pyrimidine; forms nucleoside
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Co-A, FAD, NAD
uses nucleotides
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ATP, GTP
used by prot kinases to cov mod prot; E sources
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UDP-glucose
activated intermed in glycogen and glycoprot synth
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cAMP, cGMP
IC 2nd messengers of hormones
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ATP function
inhibits glycolytic enz
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Precursors of pyrimidine synth
Bicarb, ammonium, aspartate
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end products of pyrimidine synth
- CTP: RNA synth
- dCTP: DNA synth
- TMP: DNA synth
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carboamoyl phosphate synthetase 2
inhib by UTP
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orotidylate decarboxylase
inhib by UMP, CMP
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CTP synthetase
inhib by CTP
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precursors for purine synth
aspartate, CO2, glycine, glutamine, N10-formyl tetrahydrofolate, R5P
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End products of purine synth
- ATP, GTP: RNA synth, prot synth, energy, metabolic intermed
- dATP, dGTP: DNA synth
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PRPP synthetase
- inhib by IMP, AMP, GMP
- act by PRPP
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amidophosphoribosyltransferase
inhib by IMP, AMP, GMP
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IMP->adenylosuccinate
inhib by AMP
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Dihydrofolate
prod of thymidine synthetase (dTMP production) that is converted to tetrahydrofolate via dihydrofolate reductase; drug target to prevent NA synth
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hyperuricemia
increased uric acid in serum (serum urate); causes precip of urate crystals
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arthritis
caused by precip of urate/uric acid; gout
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nephropathy
kidney damage/ failure; caused by uric acid stones in kidney (hyperuricemia); gout
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tophi
- focual urate deposits that are visible
- gout
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colchicine
relieves joint pain in gout
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probenecide
increases uric acid secretion from kidney; useful when hyperuricemia is due to decreased renal excretion (vs overproduction)
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allopurinol
- inhibits XO; decreases uric acid production
- increases X and HX levels (can lead to decreased PRPP levels if HGPRT intact bc inhib pathway)
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dopamine
requires purine nuc for synth; def can lead to neurological problems; prob in Lesch-Nyhan disease
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lymphocytopenia
loss of B and T lymphocytes (SCIDs)
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ADA def
SCIDs; elevated adenosine and deoxyadenosine (toxic to lymphocytes)
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orotate phosphoriboysel transferase and/or orotidylate carboxylase def
blocks UTP, CTP prod; in hereditary orotic aciduria
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uridine/cytidine therapy
in hereditary orotic aciduria; inhib carbamoyl phosphate synthetase 2 (decreases orotate synth), improvement of anemia and decreased orotate secretion
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5-fluorouracil (5-FU)
inhib thymidylate synth, anti-cancer drug
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hydroxyrea (HU)
inhib ribonucleotide reductase, anti-cancer drug
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6-mercaptopurine (6-MP)
inhib de novo purine biosynth, anti-cancer drug
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methotrexate (MTX)
inhib dihydrofolate reductase, anti-cancer drug
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mycophenolic acid
inhib inosine monophosphate dehydrogenase in prolif T/B cells; prevents graft rejection
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folic acid
not synth in humans (have to get it from diet) but IS synth in bact
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Sulfa drugs (sulfonamides)
comp inhib in folic acid synth; therefore we can selectively inhib purine synth in bact and not affect our own purine synth
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emulsion droplets
lipase converts TAGs to emulsion droplets; increases SA:V ratio
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bile
from liver; in gall bladder until we eat a meal, then it is released; bile acids are derivatives of cholesterol and act as detergents; mixes w/ FA and MAG in duodenum to form micelles (hence detergent property)
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chylomicron
carries TAGs in blood until reaches delivery site
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TAG lipase
- activated by adrenaline, glucagon, ACTH
- inhibited by insulin
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carnitine acyltransferase 1
RLS; FA CoA to FA carnitine to go across mitochondria
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carnitine
metabolite of lysine; adds to FA CoA to carry it across mitochondrial membrane so beta oxidation can occur
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branched FA breakdown
mitochondria, ER, peroxisomes
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Biotin
needed in propionyl CoA carboxylase
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hydroden peroxide
in v. long chain FA breakdown; acyl dehydrogenase makes hydrogen peroxide
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lots of acetone in breath
in diabetics and hungry people because low blood sugar therefore low OAA and acetyl CoA build up so ketogenesis is used; but if ketone bodies build up the ketoacidosis
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phosphopantetheine
in ACP; prosthetic group
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acetyl CoA carboxylase
RLS of FA biosynthesis
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AMPK
inactivates acetyl CoA carboxylase; inhib by ATP and act by AMP
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protein phosphatase 2A
activates acetyl CoA carboxylase via dephosphorylation; inhib by PKA and act by insulin
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PKA
- act by adrenaline
- inhib by glucagon
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citrate
binds allosterically to Acetyl CoA carboxylase
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desaturation of FA enzyme complex
NADH->NADH cytochrome b5 reductase->cytochrome b5->desaturase->stearoyl CoA
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MCAD deficiency
lesions in med chain acyl dehydrogenase (in FA oxidation); accumulation of FA such as octanoic acid
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Zellweger syndrome
no peroxisomes; can't metab FA or lipids
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X-linked Adrenoleukodystrophy
mut in v. long chain acyl CoA dehydrogenase; accumulation of FA such as hexanoic acid
rx: lorenzo's oil
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Lorenzo's Oil
rx for x-linked adrenoleukodystrophy
- glyceryl trioleate
- glyceryl trierucate
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pepsinogen
pepsin; autoact when in acidic stomach env, conf change lets it digest itself...given molecule of protein acts on itself
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pancreatic dig enz
serine proteases (trypsin, chymotrypsin, elastase, blood coagulation, complement factors)
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salt link
in pancreatic dig enz activation; phobic N chain makes a salt link w/ Asp or Glu in AS
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enteropeptidase
duodenal; cleavs trypsinogen
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tyrpsin
- autocatalysis
- cleaves panc enz prot
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Ser 195
chymotrypsin, charge relay system
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Asp 194
chymotrypsin; neg beta carboxyl forms salt linke w/ Ilu 16
can be replaced by Glu; mainly conserved
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Gly 193
Amid H forms H bond w/ substrate; in wrong position until activation; chymotrypsin
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Met 192
chymotrypsin; side chain covers subst spec pocket and prevents subst binding
ONLY VARIABLE AA: can be exchanged for Lys, Gln, Glu, Arg; charge and polarity obvs not important but SIZE is..want a medium sized side chain
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Cys 191
chymotrypsin; disulfide keeps turning force confined ot sm area...allows gtr effect of mvmt of above residues
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chymotrypsinogen
192: Met
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pancreatic trypsin inhibitor
inhibits trypsin act inappropriately
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alpha 1-antitrypsin
usually has Met to fit into subst spec pocket of elastase and inhibit elastase..prevents premature activation of elastase which eats lung tissue
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met sulfoxide
tobacco smoke; oxidized met; no longer fits in subst spec pocket of elastase...no inhibition and elastin of lung alveoli is eaten...emphysema
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procollagenase
premature activation leads to arthritis
bact cleave it in periodontitis and collagen degraded
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prekallikrein
cleaved into kallikrein via XIIa and Hmwk in intrinsic coagulation pathway
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alpha macroglobulin
traps proteolytic coagulation enz; enz cleaves alpha cov bond and results in loss of protective oligos and now BOTH enz and alpha sent to liver
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thioester
alpha 2 macroglobulin, C3, C4
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antithrombin III
inhibits thrombin (+) when activated by heparin (-)
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alpha 1 antitrypsin, TF inhib, serpin, protein Z
inhib blood coagulation
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APC
thrombin + thrombomodulin + C
eats Va and VIIIa
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LPA
- correlated w/ cholesterol intake
- competes w/ plasminogen for fibrin binding and stabilizes clot formation
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vitamin K
in gamma carboxyglutamate (adheres Ca to VII, IX, X, prothrombin, Prot C)
similar in structure to dicumarol and warfarin drugs...inhibits coagulation
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Von Willebrand factor
helps VII and platelets to interact
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DAF
on membranes of RBCs; accelerates C3b + H + I to inhibit complement activation so RBCs are not destroyed
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paroxysmal nocturnal hemoglobinuria
lacks DAF
infection results in red urine at night bc path presence creates lots C3b and binds to RBCs...RBC lysis
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p-aminobenzoate
group in THF
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gluatmate (carb metab)
group in THF
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folate
only in diet, makes THF
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sulfanilamide
inhib folate synth via pABA
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ser transhydroxy methylase
Ser-gly in N5,N10 methylene THF prod
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formyl THF synthase
THF-N10 formyl THF
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N10 formyl THF
- most oxidative carbon group
- purine synth
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fluroruracil
conv to flurordeoxyuridylate
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flurorodeoxyuridylate
suicide inhib of thymidylate synthase
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aminopterin
inhib DHFR...no THF made
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methotrexate
inhib DHFR, no THF made
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lipids (carb)
SAM acceptor
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methionine synthase
needs biotin, homocystein->methionine, THF
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cobalamin
aka B12, only made by anaerobic bact
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5'-deoxyadenosyl cabalmin
aka coenz B12, gives radical for methylmalonyl CoA mutase to make succinyl CoA
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hematopoeisis (carb)
affected by B12 def; lack of THF for DNA biosynth
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anemia (carb)
due to B12 def...no THF...no DNA synth
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6th ligand
B12; cyano, methyl, hydroxy, coenz B12
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acidosis, no myelin
methylmalonyl CoA metab mistakes
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methylmalonic acid
in urine; due to lots L-methyl malonyl CoA in methylmalonyl CoA metab mistakes
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alzheimers, MS
due to B12 def...lots methylmalonyl CoA...blocks FA synth aka myelin
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pernicious anemai
to due to IF in B12 def
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