B1U4 nucleotide metabolism 2

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CO2, aspartate, glutamine

building blocks of pyrimidines

second

all ring atoms are present after ____ step

after the ring is formed

in contrast to purine synthesis, ribose is added _______

PRPP.

The source of the ribose in pyrimidine biosynthesis

UTP, CTP, and TMP.

The three major end products of pyrimidine biosynthesis

carbamoyl phosphate synthetase II

enzyme of step 1

orotic acid

first pyrimidine

OMP - orotidine monophosphate

first pyrimidine nucleotide

UMP

first major end product of pyrimidine biosynthesis

3

first __ enzymes part of a single protein

CPS II, ATC, DHO

enzymes of CAD

orotate phosphoribosyl transferase and orotidylic acid decarboxylase (UMP synthase)

enzymes of UMP synthase

glutamine

UTP => CTP : amino donor

Ribonucleotide reductase-

UDP => dUDP : enzyme

thymidylate synthase

dUMP => TMP: enzyme

UTP on carbamoyl phosphate synthetase II

feedback inhibition of pyrimidine biosynthesis

Compartmentation: two pools of carbamoyl phosphate in mito and cytosol. Metabolic channeling: first three steps catalyzed by same protein, CAD.

feedback inhibition limited to CPS II and not CPS I

, carbamoyl phosphate synthetase II,

committed step of pyrimidine biosynthesis

CTP synthetase

_____________ uses glutamine as the amino donor and is inhibited by glutamine analogs

5-fluorouracil (5-FU)

is an effective inhibitor of thymidylate synthesis.

FdUMP

5-fluorouracil is converted in the cell into ____________

binds irreversibly to the active site of thymidylate synthase, thereby inactivating the enzyme and blocking thymidylate synthesis.

method of FdUMP

block DNA synthesis (block cell growth, cause cell death)

result of blocking thymidylate synthesis

CO2, NH3, beta-aminoisobutyrate

3 end products of pyrimidine catabolism

beta-aminoisobutyrate

can be an indicator of DNA degredation and cell death if found in urine in high levels

Hereditary Orotic Aciduria

Symptoms: megaloblastic anemia, growth retardation, excess orotic acid in urine

Hereditary Orotic Aciduria

The primary clinical problems are due to lack of pyrimidines for DNA and RNA synthesis in rapidly dividing cells.

orotidine-5'-P pyrophosphorylase (orotate phosphoribosyl transferase) and orotidine-5'-P decarboxylase

Deficiency in Hereditary Orotic Aciduria

lack of pyrimidines for DNA and RNA synthesis in rapidly dividing cells.

The primary clinical problems in Hereditary Orotic Aciduria are due to

oral Uridine (which goes to UTP)

treatment for Hereditary Orotic Aciduria

ribonucleotide reductase

All four ribonucleotides are converted by the same enzyme

T=thioredoxin T(SH)2

source of reducing power for ribonucleotide reductase

dATP

inhibits at the general activity site.

dGTP and dTTP

act as inhibitors at the specificity site, by inhibiting reduction of pyrimidine nucleoside diphosphates

: dTTP, from thymidine, inhibits reduction of pyrimidine nucleoside diphosphates (Pool of dCTP decreased 10-fold)

Why do high levels of thymidine arrest growth of cells?

Thymidylate synthase (not directly from ribonucleotide reductase like dADP, dGDP, dCDP, and dUDP)

dTMP is derived from methylation of dUMP by

phosphoribosyl transferase and nucleoside phosphorylase/nucleoside kinase

two types of salvage pathways

Adenine (APRT), Guanine/Hypoxanthine (HGPRT), Uracil (UPRT) and none of cytosine

phosphoribosyl transferases

HGPRT

enzyme deficient in Lesch-Nyhan

Lesch-Nyhan

increased uric acid with self-mutilation and mental retardation

brain relies upon salvage pathways for nucleotides

reason for neurological problems in Lesch-Nyhan

PRPP

sugar added in slavage pathways (phosphoribosyl transferase type)

turns it up. PRPP used for purine synthesis instead of salvage pathway

result of HGPRT deficiency on purine synthesis

uracil and thymine only

bases 2nd type (w/ kinase - 2 steps) of salvage pathway works with

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