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