Purine and Pyrimidine Breakdown and Heme Flashcards
Ribonucleotides are the Precursors
of
Deoxyribonucleotides
converts ribonucleotides to deoxyribonucleotides
ribonucleotide reductase
intermediate hydrogen-carrying protein that carries a pair of hydrogen atoms from NADPH to the ribonucleoside diphosphate
has pairs of –SH groups that carry hydrogen atoms
thioredoxin
catalyzes the reduction of the oxidized form of thioredoxin by NADPH
thioredoxin reductase
transfers reducing power from glutathione (GSH) to ribonucleotide reductase
glutaredoxin
electrons are transmitted to the enzyme from NADPH via
glutaredoxin or thioredoxin
Regulation of E. coli
Ribonucleotide Reductase
Each α subunit has two types of regulatory sites:
- one type affects overall enzyme activity
- ATP activates the enzyme
- dATP inactivates the enzyme
- one type alters substrate specificity in response to the effector molecule that is bound
- ATP or dATP favors reduction of UDP and CDP
- dTTP favors reduction of GDP
- dGTP favors reduction of ADP
Regulation of Ribonucleotide Reductase by Deoxynucleoside Triphosphates
provides a balanced pool of precursors for DNA synthesis
Thymidylate is derived from:
dCDP and dUDP
- the immediate precursor of thymidylate (dTMP) is dUMP
- in bacteria, a dUTPase converts dUTP to dUMP
- dUTP forms by deamination of dCTP or by phosphorylation of dUDP
catalyzes the conversion of dUMP to dTMP
a one-carbon unit is transferred from N5,N10-methylenetetrahydrofolate to dUMP, then reduced to a methyl group
thymidylate synthase
reduces dihydrofolate to tetrahydrofolate
dihydrofolate reductase
Folic Acid Deficiency Leads to
Reduced thymidylate synthesis
folic acid deficiency occurs in __________ of the human population
and up to ________ of people in impoverished communities
10%; 50%
reduced thymidylate synthesis cause ______to be incorporated into DNA
uracil
repair mechanisms remove the uracil by creating strand breaks that affect the structure and function of DNA and is associated with:
cancer, heart disease, and neurological impairment
Degradation of Purines and Pyrimidines produces:
Uric acid and urea respectively
removes the phosphate from purine nucleotides
adenylate yields adenosine
5’-nucleotidase
deaminates adenosine to inosine
adenosine deaminase
inosine is hydrolyzed to:
oxidized to:
hypoxanthine
xanthine
GMP Catabolism
- GMP is first hydrolyzed to guanosine, which is then cleaved to free guanine
- guanine undergoes hydrolytic removal of its amino group to yield xanthine
flavoenzyme that catalyzes the oxidation of xanthine to uric acid
xanthine oxidase
contains an atom of molybdenum and four iron-sulfur centers in its prosthetic group
molecular oxygen is the electron acceptor
Catabolism of Purnine Nucleotides
Catabolism of Pyrimidines:
- pathways for degradation lead to NH4+ production and thus to urea synthesis
- carbons of thymine are degraded to succinyl-CoA
- carbons of cytosine and uracil are degraded to acetyl-CoA
leads to a 100-fold increase in [dATP], a strong inhibitor of ribonucleotide reductase
causes severe immunodeficiency disease in which T lymphocytes and B lymphocytes do not develop properly
produces a general deficiency of other dNTPs in T lymphocytes
adenosine deaminase (ADA) deficiency
free purines can be salvaged and rebuilt into
nucleotides
catalyzes the reaction of a free adenine with PRPP to yield the corresponding adenine nucleotide
adenine + PRPP → AMP + PPi
adenosine phosphoribosyl-transferase
catalyzes the salvage of free guanine and hypoxanthine (the deamination product of adenine)
hypoxanthine-guanine phosphoribosyltransferase
set of symptoms characterized by poor coordination, intellectual deficits, hostility, and compulsive self-destructive tendencies
caused by a genetic lack of hypoxanthine-guanine phosphoribosyltransferase activity
Lesch-Nyhan syndrome
- a disease of the joints caused by an elevated concentration of uric acid in the blood and tissues
- often involves an underexcretion of urate
- genetic deficiency of one or another enzyme of purine metabolism may also be a factor
gout
inhibitor of xanthine oxidase that is used in the treatment of gout
allopurinol
at the active site, allopurinol is converted to
oxypurinol, a strong competitive inhibitor
remains tighlty bound to the enzyme
Many chemotherapies agents target enzymes in
specific targets include:
Nucleotide Biosynthetic Pathways
thymidylate synthase and dihydrofolate reductase, enzymes that provide the only cellular pathway for thymine synthesis
Thymidylate Synthesis and Folate Metabolism
agent that is converted to the deoxynucleoside monophosphate FdUMP in salvage pathways
fluorouracil
FdUMP binds and inactivates
thymidylate synthase
- a folate analog that acts as a competitive inhibitor of dihydrofolate reductase
- used as a chemotherapeutic agent
- aminopterin is a related compound that acts similarly
methotrexate
- an antibiotic that binds to bacterial dihydrofolate reductase nearly 100,000 times better than to the mammalian enzyme
- treats certain urinary and middle-ear bacterial infections
trimethoprim
Glycine is a precursor to______
constructed from four molecules of the monopyrrole derivative porphobilinogen (derived from two molecules of δ-aminolevulinate)
porphyrins
make up the porphyrin nucleus in heme proteins
Porphyrin synthesis id feedback inhibited by heme which is the end-product of the heme synthesis pathway
Biosynthesis of δ-Aminolevulinate in Higher Eukaryotes
glycine reacts with succinyl-CoA in the first step to yield α-amino-β-ketoadipate, which is then decarboxylated to δ-aminolevulinate
Two Major Pathways to δ-aminolevulinate
Biosynthesis of Protoporphyrin
- porphobilinogen = formed from two molecules of δ-aminolevulinate
-
protoporphyrin = formed from four molecules of porphobilinogen
- iron is incorporated after assembly
-
porphyrias = human diseases caused by genetic defects in the biosynthesis of porphyrins
- leads to the accumulation of pathway intermediates
Biosynthesis of Heme From δ-aminolevulinate
Heme Degradation Has Multiple Functions
- degradation of iron-porphyrin (heme) generates bilirubin, which is converted to bile pigments
- breakdown pathways protect cells from oxidative damage
humans have at least _______ isozymes of heme oxygenase (HO)
three
expression of HO-1 is induced by stress conditions:
- shear stress
- uncontrolled angiogenesis (development of blood vessels)
- hypoxia and hyperoxia
- heat shock
- ultraviolet light
- hydrogen peroxide
- expression of HO-2 is found in ________ where it is continually expressed
- HO-3 [is/is not] catalytically active…, but may play a role in _________.
brain and testes
is not; oxygen sensing
