Purine and Pyrimidine Synthesis and Degradation
what is 5-phosphoribosyl-1-pyrophosphate?
PRPP
nucleotide kinase
UMP + 2 ATP --> UTP
what is the gist of purine de novo synthesis?
amino acids are broken down and use to build a nucleotide
purine de novo synthesis pathways uses _______ _________ and produces ____________
amino acids, nucleotides
what 4 molecules are involved in de novo synthesis of nucleotides?
amino acids, ribose-5-phosohate, CO2 and NH3
describe pyrimidine de novo synthesis
base is synthesized first, then it is attached to a ribose-5-phosphate moiety
what type of bond links a base and pentose sugar in a nucleoside? does it rotate?
beta-glycosidic, yes
What is the CAD complex?
carbamoyl phosphate synthetase II (CPS II) aspartate transcarbamoylase dihydroorotase
phosphoribosyl transferases
catalyze the addition of a ribose-5-phosphate from PRPP to a free base adenine phosphoriboxy transferase (APRT) hypoxanthine-guanine phosphoriboxyl transferase (HGPRT) generates a nucleotide and and pyrophosphate
thymidylate synthase
catalyzes the conversion of dUMP to dTMP the methyl donor is FH4
purine nucleoside phosphorylase
catalyzes the reaction of the N-glycosidic bond in guanosine and iosine converts guanosine and inosine to guanine and hypoxanthine, respectively, and ribose-1-phosphate
dihyroorotase
converts N-carbamoylaspartate to L-dihydroorotate
aspartate transcarbamoylase
converts carbamoyl phosphate and aspartate to N-carbamoylaspartate feedback inhibition by UTP
orotate phosphoribosyl transferase
converts orotate and PRPP to orotidylate driven by hydrolysis of PPi orotidylate is a nucleotide
orotidylate decarboxylase
converts orotidylate to uridylate (UMP)
PRPP synthetase
converts ribose-5-phosphate to PRPP attaches a phosphate group participates in BOTH purine and pyrimidine synthesis feedback inhibition by ADP and GDP
what are the deoxyribonucleo*t*ides of A, G, T and C called?
dAMP, deoxyadenylate dGMP, deoxyguanylate TMP, thymidylate dCMP, deoxycytidylate
IMP is synthesized during ________________ of purines
de novo synthesis
adenosine deaminase
degrades adenosine to inosine
guanine deaminase
degrades guanine to xanthine
nucleosidase
degrades guanosine to guanine
xanthine oxidase
degrades xanthine to uric acid rate limiting step of purine degradation
what are the deoxyribonucleo*s*ides of A, G, T and C called?
deoxydenosine, deoxyguanosine, thymidine, deoxycytidine
primary gout is caused by what?
enzymes defects in the purine degradation pathway
what bond type binds the first phosphate to the pentose sugar of a nucleotide?
ester linkage to the 5' OH of the pentose
_____ pyrimidine bases are salvaged in human cells (think frequency)
few
adenyosuccinate synthetase
first step in the conversion of IMP to AMP overall reaction adds an amine from aspartate feedback inhibition by AMP
IMP dehydrogenase
first step in the conversion of IMP to GMP overall reaction oxidizes and adds an amine group from glutamine feedback inhibition by GMP
what is the first committed purine de novo synthesis?
glutamine donates an amino group (becomes N9) to C1 of PRPP, release of PPi drive the reaction catalyzed by glutamine-phosphoridosyl amidotransferase (feedback inhibition of AMP, GMP and IMP)
how does methotrexate work?
inhibits dihydrofolate reductase so that FH+ cannot donate a methyl group to dUMP inhibits thymidine synthesis, and cell proliferation
what is the first committed step of pyrimidine de novo synthesis?
involves the CAD complex
nucleo*s*ides
nitrogenous base linked to a pentose sugar
in the liver, nucleotides can be converted to __________ or free ______ to be used in salvage pathways
nucleosides or free bases
nucleo*t*ides
one or more (up to 3) phosphate groups linked to a nucleotide
adenine
purine DNA and RNA
guanine
purine DNA and RNA
what are the 3 major enzymes of the purine salvage pathways?
purine nucleoside phosphorylase phosphoriboxyl transferases deaminases
compare and contrast de novo purine synthesis with that of pyrimidines
purines: heterocyclic rings are synthesized one atom at a time, first atom attached to ribose phosphate (source is PRPP) and then all the other atoms are added pyrimidines: common intermediate, orotate, synthesized first, then orotate is attached to ribose phosphate (source is PRPP)
thymine
pyrimidine DNA
cytosine
pyrimidine DNA and RNA
uracil
pyrimidine RNA
describe salvage pathways
recycling of free bases and nucleosides from nucleic acid breakdown
5'-nucleotidase
removes a phosphate group
nucleoside kinases
salvage pyrimidine nucleosides by utilizing ATP and phosphorylating them
what is more energy efficient, the purine de novo or salvage pathway?
salvage, because the de novo synthesis of the purine requires at least 6 high-energy bonds, whereas salvage converts free bases and nucleosides to nucleotides
adenylosuccinate lyase
second step in the conversion of IMP to AMP overall reaction adds an amine from aspartate
XMP-glutamine amidotransferase
second step in the conversion of IMP to GMP overall reaction oxidizes and adds an amine group from glutamine
what are the manifestations of adenosine deaminase deficiency?
severe combined immunodeficiency syndrome (SCID) both T and B cells are deficient accumulation of their precursors leads to toxic effects "baby in a bubble"
carbamoyl phosphate synthetase II (CPS II)
synthesizes carbamoyl phosphate inhibited by UTP activated by PRPP
what organ, besides the liver, also produces a significant amount nucleotides?
the brain
where does gout manifest? why?
the foot, more uric acid precipitates at colder temperatures
where does most de novo synthesis occur?
the liver
during pyrimidine de novo synthesis, what UDP is converted to dUDP to what?
thymidylate (dTMP) (UDP converted to dUDP by ribonucleotide reductase)
gout is an accumulation of what in the bloodstream
uric acid
what are purines degraded to?
uric acid
what is the treatment of gout?
xantine oxidase inhibitors NSAIDs corticosteroids uricosuric drugs
what is an HGPRT deficiency?
Lesch-Nyhan syndrome X-linked recessive disorder cannot salvage hypoxathine or guanine which results in excessive amounts of uric acid production and accumulation in the joints
what are some xanthine oxidase inhibitors?
allopurinol, febuxostat
how are nitrogenous bases and nucleosides transported to tissues?
RBCs
what N on a pyrimidine is linked to pentose sugar in a nucleotide? to what carbon of the pentose sugar?
3, 1
what N on a purine is linked to pentose sugar in a nucleoside? to what carbon of the pentose sugar?
9, 1
IMP is a precursor of _____ and ______
AMP, GMP
what are the ribonucleo*t*ides of A,G, U and C called?
AMP, adenylate GMP, guanylate UMP, uridylate CMP, cytidylate
serine hydroxymethyl transferase
FH4 receives a methyl group from serine
cytidylate synthetase
UTP + glutamine --> CTP + glutamate
what are some manifestation of Lesch-Nyhan syndrome (LNS)?
accumulation of uric acid in joints, spastic movements, mental retardation and impulse to self mutilate
deaminases
adenosine and AMP may be deaminated by adenosine deaminaase (ADA) and AMP deaminase respectively to form inosine and IMP
what are the ribonucleo*s*ides of A, G, U and C called?
adenosine, guanosine, uridine and cytidine
secondary gout is caused by what?
alcohol use, renal insufficiency, drugs that cause hyperuricemia
how do you treat Lesch-Nyham syndrome (LNS)?
allopurinol no cure