39. Purine and Pyrimidine Metabolism

Overproduction of xanthine oxidase can be due to overactivity of ____ (enzyme) or deficiency of ____ (a purine salvage enzyme)

Overproduction of xanthine oxidase can be due to overactivity of PRPP synthetase or deficiency of HGPRT (a purine salvage enzyme)

IMP, AMP and GMP will inhibit the synthesis of ____ and _____ AMP and GMP will also inhibit the first step in their synthesis from ____

IMP, AMP and GMP will inhibit the synthesis of PRPP (PRPP synthetase) and PRA (Glutamine-PRPP amidotransferase) AMP and GMP will also inhibit the first step in their synthesis from IMP

Lesch-Nyhan syndrome is due to a deficiency in _____ enzyme --> the result is ____ bases cannot be salvaged --> this leads to an increase in ____ levels

Lesch-Nyhan syndrome is due to a deficiency in HGPRT enzyme --> the result is purine bases cannot be salvaged --> this leads to an increase in uric acid levels

Nucleic acids are broken down to _____ via ____ (enzymes)

Nucleic acids are broken down to mononucleotides via nucleases Mononucleotides are further broken down into --> nucleosides --> bases Bases can be salvaged or degraded

What are two main reason why we don't want to break down purines and rather salvage them?

1. They take a lot of energy to be made --> don't want to waste this energy 2. They by-products of break down can be toxic (uric acid)

What are the 3 atom sources for pyrimidine synthesis? (note: 2 AA's are used) What are 3 major pyrimidines? What's different about pyrimidine synthesis is that it forms the ____ first rather than the ____ structure (like in purine synthesis)

3 atom sources for pyrimidine: - Aspartate (same as purine) - Glutamine (same as purine) - HCO3- 3 major pyrimidines: - Cytosine - Thymine - Uracil What's different about pyrimidine synthesis is that it forms the base first rather than the ring structure (like in purine synthesis)

What are the 5 atom sources of purines? (note: 3 of them are AA's and 2 are carbon sources) What are the 2 purines? When purines are broken down they form _____

5 atom sources of purines: - Aspartate - Glycine - Glutamine - CO2 - formyl-TH4 2 major purines: - Adenine - Guanine When purines are broken down they form uric acid (can toxic and can contribute to gout)

_____ (1) inhibits thymidylate synthase ____ (1) can be used to treat ____ and ____ cancer

5-fluorouracil (5-FU) (1) inhibits thymidylate synthase 5-fluorouracil (5-FU) (1) can be used to treat leukemia and colon cancer

____ (drug) is found to ____ inhibit xanthine oxidase

Allopurinol (drug) is found to competitively inhibit xanthine oxidase Note: how it inhibits xanthine oxidase at two places --> inhibits hypoxanthine to xanthine --> also inhibits xanthine into uric acid

Allopurinol via ____ (enzyme) is converted to _____ in cells to be an inhibitor of xanthine oxidase Note: NAD+ is used here

Allopurinol via xanthine dehydrogenase is converted to oxypurinol in cells to be an inhibitor of xanthine oxidase Note: NAD+ is used here

Describe what contributes to gout and how the blood pH plays a role in this.

Blood pH is 7.4 --> thus when uric acid is in the blood it is in its protonated form --> this form of uric acid is not soluble --> it will form crystal aggregates at areas of low blood flow --> such as synovial lining of joints and of the big toe

Degradation of purine bases: Occurs mainly in the _____ GMP forms _____ which can then form _____ AMP forms ____ then _____ then _____ The pathways for degradation of AMP and GMP merge at the point where ____ is formed

Degradation of purine bases: Occurs mainly in the liver GMP forms guanosine which can then form guanine AMP forms IMP then inosine then hypoxanthine The pathways for degradation of AMP and GMP merge at the point where xanthine is formed

Deoxythymidylate (dTMP) (required for DNA synthesis) is formed by _____ of dUMP by the enzyme ______

Deoxythymidylate (dTMP) (required for DNA synthesis) is formed by methylation of dUMP by the enzyme thymidylate synthase Note: Methylene-TH4 is used as the carbon source

____ is the first nucleotide formed from purine synthesis

IMP (inosate) is the first nucleotide formed from purine synthesis

IMP can be converted into either ____ or ____

IMP can be converted into either AMP (adenylate) or GMP (guanylate) Note: AMP and GMP can then be phosphorylated to their di- and tri-phosphates, then used for RNA synthesis.

Purine and pyrimidines are synthesized _____ using ____ as precursors --> this occurs in the _____ Lots of ____ is used as well Purine bases are built on the ____ moiety

Purine and pyrimidines are synthesized de nova using AA as precursors --> this occurs in the liver Lots of ATP is used as well Purine bases are built on the ribose moiety (ribose-5-phosphate)

Purine synthesis PRPP is made into PRA this is known as the _____ step Describe what is the nitrogen donor here as well as the enzyme catalyzing this.

Purine synthesis PRPP is made into PRA this is known as the committed step Glutamine is the nitrogen donor (forms glutamate after) Glutamine-PRPP amidotransferase is the enzyme catalyzing this reaction

Purine synthesis Ribose-5-phosphate is phosphorylated via ____ to form ______ What enzyme is used to catalyze this reaction?

Purine synthesis Ribose-5-phosphate is phosphorylated via ATP to form PRPP PRPP synthetase catalyzes this reaction

How is the synthesis of purines regulated?

Purine synthesis is regulated via negative feedback inhibition

Pyrimidine synthesis After subsequent steps Orotate (the base) is formed Orotate is converted to Orotidylate via _____ (enzyme) --> ____ (molecule) is added to from the ring structure Orotidylate is then converted into _____ via ____ (enzyme)

Pyrimidine synthesis After subsequent steps Orotate (the base) is formed Orotate is converted to Orotidylate via orotate phosphoribosyl-transferase --> PRPP (molecule) is added to from the ring structure Orotidylate is then converted into Uridylate (UMP) via orotidylate decarboxylase

Pyrimidine synthesis Step 1: Glutamine is made into _____ This requires ____ (enzyme), ____ (molecule) and 2 ATP's

Pyrimidine synthesis Step 1: Glutamine is made into carbamoyl phosphate This requires CPS II (carbamoyl phosphate synthetase), HCO3- (which is converted to glutamate) and 2 ATP's

Reduction of Ribonucleotides to Deoxyribonucleotides For DNA synthesis, ribose is reduced to deoxyribose by the enzyme ____ which requires the protein _____ Reduction to deoxyribose occurse at the nucleotide ____ level

Reduction of Ribonucleotides to Deoxyribonucleotides For DNA synthesis, ribose is reduced to deoxyribose by the enzyme ribonucleotide reductase which requires the protein thioredoxin Reduction to deoxyribose occurse at the nucleotide diphosphate level

Salvage of bases Adenine can be salvaged into _____ via _____ enzyme and the addition of ____ molecule

Salvage of bases Adenine can be salvaged into AMP via adenine phosphoribosyl-transferase enzyme and the addition of PRPP molecule

Salvage of bases Hypoxanthine can be salvaged into ____ Guanine can be salvaged into ____ Both of these salvaging reactions uses ____ enzyme to add _____ (molecule) onto hypoxanthine/guanine

Salvage of bases Hypoxanthine can be salvaged into IMP Guanine can be salvaged into GMP Both of these salvaging reactions uses hypoxanthine guanine phosphoribosyl-transferase to add PRPP (molecule) onto hypoxanthine/guanine

UMP is converted into CTP (cytosine nucleotide) in three steps UMP is first converted into ___ and ___ via the addition of phosphate groups from _____ UTP is then made into CTP via ____ (enzyme) - ____ is a nitrogen source - ATP is also used UTP and CTP can be used for RNA synthesis

UMP is converted into CTP (cytosine nucleotide) in three steps UMP is first converted into UDP and UTP via the addition of phosphate groups from ATP UTP is then made into CTP via CTP synthetase - glutamine is a nitrogen source (made into glutamate after) - ATP is also used UTP and CTP can be used for RNA synthesis

Xanthine can be converted to ____ acid via _____ (enzyme)

Xanthine can be converted to uric acid via xanthine oxidase

Xanthine oxidase is also used to convert ____ into xanthine

Xanthine oxidase is also used to convert hypoxanthine into xanthine