Kinde- Nucleotide & AA Metabolism Flashcards
Define Hartnup Disease
Defective transport of nonpolar AA (tryptophan)
What are the symptoms of Hartnup Disease?
Pellagra-like dermatosis, photosensivity, nystagmus, tremors
Define Cystinuria
Defective transport of dibasic AAs (COAL). Symptoms: nephrolithiasis (kidney stones)
Which AAs are keotgenic only?
Lysine & leucine
Metabolized into Acetyl CoA or Acetoacetate directly for eventua; FA synthesis
Which AAs are keotgenic & glutogenic?
Phe, Ile, Trp, Tyr, Thr (PITTT)
What do glucogenic AAs do?
Metabolized into pyruvate or TCA intermediates directly for eventual glucose synthesis
Define homocystinuria (what it is, symptoms, what it affects)
Type I: transsulfuration (Cystathionine B-synthase, PLP from B6)
Type II/III: methylation (homocysteine methyltranferase)
Autosomal recessive enzymatic deficiencies or nutritional deficiencies (B6, B12, folic acid)
Affects eyes (lens discoloration), skeleton (long limbs), CNS (dementia), vascular (stroke)
Define MSUD` (what it is, symptoms, what it affects)
Maple syrup urine disease
Deficiency in branched chain alpha-ketp acid dehydrogenase (Val, Ile, Leu)
Accumulation of toxic metabolites leads to cognitive dysfunction, failure to thrive, low tone, hallmark MS smell, limit ingestion of BCAA with diet of synthetic proteins
Define phenylketonuria` (what it is, symptoms, what it affects)
Deficient phenylalanine hydroxylase (primary PKU) leads to accumulation of toxic metabolites
Cognitive malfunction, musty smell in urine
Limit dietary Phe & supplement with Tyr
What happens in a prolonged depletion of tyrosine?
Production of catecholamines & melanin is affected. More profound cognitive dysfunction, pigment dilution in skin, hair, eyes
How is ammonia removed from the muscles?
By alanine. Pyruvate is formed from glucose via glycolysis. Aminotransferase rxn to form Ala from pyruvate via ALT. Alanine shuttles to liver to undergo aminotransferase rxn (via ALT) to form Glu –> urea cycle via glutamate dehydrogenase
How is ammonia removed from the brain?
By glutamine.
Define hyperammonemia.
Ammonia toxicity from hepatic insufficiency or disorders in urea cycle
Swelling of astrocytes due to increased glutamine formation from glutamate (can lead to cerebral edema, intracranial hypertension which is most common cause of death in acute liver failure)
Autosomal recessive. with exception to deficiencies in ornithine transcarbamoylase
What are the 4 phases of De Novo synthesis of purines?
Phase I: activation of ribose 5-P to active form, PRPP (upreg by Pi, downreg by GMP, AMP, IMP)
Phase II: conversion of PRPP into PRA (committed step, upreg by PRPP, downreg by GMP, AMP, IMP)
Phase III: Construction of IMP (9-step ring-constructing sequence, consumes eq. 4 ATP, downreg by methotrexate)
Phase V: IMP –> ATP & GTP
What are the 3 phases of De Novo synthesis of pyrimidines?
Phase I: construction of pyrimidine ring (orotate).
-Carbamoyl phosphate synthetase II. RLS. Downreg by UMP/UTP. Upreg by PRPP
-Aspartate transcarbamoylase (ATCase). downreg by CTP
Phase II: orotate + PRPP –> UMP. defective pathway leads to orotic aciduria without hyperammonedmia
Phase III: UMP –> CTP & dTMP. dUDP loop tp keep dUTP low to prevent incorporate into DNA. Downreg by 5-fluorouracil
What is methotrexate (therapy targeting nucleotide synthesis/antimetabolite)?
Antineoplastic agent used to treat cancer by targeting DNA synthesis in rapidly dividing cancer cells.
-inhibiting both purine & pyrimidine synthesis pathways
What is fluorouracil (therapy targeting nucleotide synthesis/antimetabolite)?
Antineoplastic agent used to treat cancer by targeting DNA synthesis in rapidly dividing cancer cells.
-inhibits pyrimidine synthesis, specifically by targeting thymidylate synthase. Depletes dTMP –> triggers cell death. Fluorouracil reacts with N-mTHF to more tightly bind with thymidylate synthase preventing rxn w/dUMP
What are sulfa drugs (therapy targeting nucleotide synthesis/antimetabolite)?
Antimicrobial agent that selectively disrupts DNA replication.
- bacteria synthesize THF using dihydropteroate synthase + PABA
- Sulfa drugs mimics PABA substrate, inhibits the enzymatic action, halts THF formation, disrupts bacterial DNA replication (pyrimidine & purine synthesis)
What is acyclovir (therapy targeting nucleotide synthesis/antimetabolite)?
Antiviral agent that is a synthetic nucleoside analogue
-viral thymidine kinase preferentially phosphorylates acyclovir for incorporation into DNA synthesis, acyclovir more closely resembles guanosine, phosphorylated acyclovir inhibits viral DNA polymerase which terminates DNA replication
Xanthine oxidase is the target for treatment of what? And why?
Gout because it limits production of uric acid bc hypoxanthine –> Xanthine –> uric acid
Adensoine deaminase (ADA) deficiency is associated with what and why?
SCID. Leads to high adenosine & low inosine. Adenosine –> AMP & ADP & then to dADP & dATP
A deficiency in what is associated with Lesch-Nyhan Syndrome?
HGPRT
Severe form of primary hyperuricemia (leads to gout, urate kidney stones, poor muscle control, severe cognitive impairment & tendency for self-mutilation)
What do salvage pathways do & what do they dominate?
Nitrogenous bases recovered during nucleotide turnover can be reincorporated into nucleotides. Dominates de novo synthesis for purines
What do APRT and HGPRT generate?
APRT: AMP
HGPRT: GMP or IMP
