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B1U4 nucleotide metabolism 2
CO2, aspartate, glutamine
building blocks of pyrimidines
all ring atoms are present after ____ step
after the ring is formed
in contrast to purine synthesis, ribose is added _______
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
OMP - orotidine monophosphate
first pyrimidine nucleotide
first major end product of pyrimidine biosynthesis
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
UTP => CTP : amino donor
UDP => dUDP : enzyme
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
_____________ uses glutamine as the amino donor and is inhibited by glutamine analogs
is an effective inhibitor of thymidylate synthesis.
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
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
All four ribonucleotides are converted by the same enzyme
source of reducing power for ribonucleotide reductase
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
enzyme deficient in 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
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