Term
|
Definition
- a pentose monosaccharide (ribose or 2’-deoxyribose) - a nitrogenous base linked by a β-glycosidic bond to the1’-carbon - one, two, or three phosphate groups |
|
|
Term
|
Definition
| the sugar and base moieties, but no phosphate groups |
|
|
Term
| what can happen as a result of an inadequate amount of folate intake (esp. during pregnanc) |
|
Definition
|
|
Term
| the first step in purine metabolism |
|
Definition
- syntehesis of 5-Phosphoribosyl-1-pyrophosphate (PRPP) from Ribose 5-phosphate
- this is carried out by PRPP synthettase which uses Mg2+ and a molecule of ATP
|
|
|
Term
| What is the activator of PRPP synthetase, and what are the Inhibitors |
|
Definition
- Activator: Pi
- Inhibitors: Purine ribonucleotides
|
|
|
Term
| What is the second step of purine metabolism |
|
Definition
- synthesis of 5'-phosphoribosylamine
- this is the "committed" and rate-limiting step of purine biosynthesis
- an amide group donated from glutamine replaces the pyrophosphate on the 1'-carbon
- configuration of C-1' is changed from alpha to beta by the reaction
- Inhibitors: AMP, GMP, IMP
- Activators: PRPP
|
|
|
Term
| What are the sources of the purine ring atoms?[image] |
|
Definition
|
|
Term
Sulfonamides (PABA analogs) |
|
Definition
- inhibit bacterial production of folic acid (folate derivatives required during purine biosynthesis)
- human cells do not produce folic acid de novo, and are thus unaffected by these drugs
|
|
|
Term
Methotrexate (folate analog) |
|
Definition
-
inhibits mammalian dihydrofolate reductase, thus depleting the N10-formyl-tetrahydrofolate required for purine synthesis -
inhibits DNA replication and cell proliferation in rapidly growing cancer cells significant toxicity issues for other rapidly proliferating tissues!!!
|
|
|
Term
Trimethoprim (folate analog) |
|
Definition
- inhibits purine biosynthesis in prokaryotes by selectively inhibiting bacterial dihydrofolate reductase
|
|
|
Term
| Conversion of IMP to AMP and GMP |
|
Definition
- IMP is the precursor of both AMP and GMP
- two reactions are required for conversion of IMP to either AMP or GMP
- IMP-->XMP-->GMP
- IMP-->Adenylosuccinate-->AMP
- the first reaction in each pathway is inhibited by the appropriate end product (AMP or GMP)
- the entire purine biosynthetic pathway is subject to extensive negative feedback control
|
|
|
Term
| How may graft rejection be prevented |
|
Definition
- by inhibiting GMP syntehesis
|
|
|
Term
|
Definition
- the drug is a reversible uncompetitive inhibitor of IMP dehydrogenase
- the drug deprives rapidly proliferating T and B cells of key components of nucleic acids
- the drug is used to prevent graft rejection
|
|
|
Term
|
Definition
- convert nucleoside monophosphates to diphosphates
- ATP is the principle phosphate donor
- does not distinguis between nucleotides containing ribose versus deoxyribose sugars
|
|
|
Term
|
Definition
- Converts nucleoside diphosphates to triphosphates
- ATP is the principal phosphate donor
- do not generaly distinguish between nucleotides containing ribose versus deoxyribose sugars
|
|
|
Term
|
Definition
- converts ribonucleotides to ribonucleotides
- 4 enzyme subunits (2 x B1 and 2 x B2)
- substrates ae nucleoside diphosphates: A/C/G/UDP --> dA/dC/dG/dUDP
- enzyme activity and substrate specificity is regulated by specific nucleotides binding to the B1 subunits
- nucleotide reduction invloves formation of a disulfide bond within the protein
|
|
|
Term
|
Definition
- regenerates reduced ribonucleotide reductase
- thioredoxin reductase then regenerates reduced thioredoxin
|
|
|
Term
|
Definition
This “salvage” pathway couples free purines to 5’-phosphoribosyl pyrophosphate (PRPP) using one of two enzymes, with loss of pyrophosphate.
Hypoxanthine-guanine phosphoribosyltransferase (HPRT): Hypoxanthine + PRPP → IMP + PPi Guanine + PRPP → GMP + PPi Adenine phosphoribosyltransferase (APRT): Adenine + PRPP → AMP + PPi |
|
|
Term
|
Definition
- lack of purine salvage
- caused by an X-linked, recessive deficiency in hypoxanthine-guanine phosphoribosyltransferase (HPRT)
- patients are unable to salvage hypoxanthine (to form IMP) or guanine (to form GMP)
- decreased IMP and GMP concentrations activate endogenous purine synthesis at the committed step
- lack of salvage and increased purine synthesis results in overproduction of uric acid leading to: (severe gout, urate kidney stones, neurological disorders)
|
|
|
Term
| what are dietary purines generally deraded to in the intestinal mucosa? |
|
Definition
|
|
Term
| Degradation of cellular purine nucleotides |
|
Definition
1.Adenine is deaminated, either as AMP→IMP, or from adenosine→inosine. ● 2.Dephosphorylation: IMP→inosine GMP→guanosine • 3.Removal of sugars: guanosine→guanine inosine→hypoxanthine • 4.Deamination of guanine gives xanthine. ● Xanthine oxidase converts hypoxanthine to xanthine – subsequent oxidation of xanthine generates uric acid, which is excreted in the urine |
|
|
Term
|
Definition
- caused by overproduction (rare) or underexcretion (common) of uric acid
- affects approximately 1 million people in the US
- leads to deposition of sodium urate in tissues, especially the kidneys and joints
- deposition of sodium urate crystals induces an inflammatory response involving granulocyte recruitment
|
|
|
Term
|
Definition
- used to treat overroduction of uric acid (Gout)
- allopurino is metabolized to form an inhibitor of xanthine oxidase
- this results in acumulation of hypoxanthine and xanthine which are much more soluble than uric acid
|
|
|
Term
| Adenosine Deaminase Deficiency (ADA) |
|
Definition
autosomal recessive loss of adenosine deaminase (ADA)
ADA deficiency prevents deamination of adenosine to inosine, resulting in accumulation of adenosine and related nucleotides (ADP, ATP, dATP, etc.)
increased dATP inhibits ribonucleotide reductase, thus depleting cellular pools of dNTPs necessary for DNA synthesis
inhibition of DNA synthesis prevents proliferation of B and T cells (among others), and is manifested as severe combined immunodeficiency disease (SCID) ADA deficiency may account for 14% of all cases of SCID in the US.
|
|
|
Term
| What is the basis of pyrimidine synthesis |
|
Definition
Unlike purines, pyrimidine bases are not assembled on a PRPP scaffold. Rather, they are constructed from basic components to form the 6-membered orotate ring, which is then transferred to PRPP. |
|
|
Term
| In mammals, synthesis of pyrimidines is principally regulated when and how? |
|
Definition
- Regulated at the first step
- Catalyzed by carbamoyl phosphate synthetase II (CPS II):
- inhibited by UTP
- activated by ATP and PRPP
|
|
|
Term
| In prokaryotes, synthesis of pyrimidines is regulated when and by what? |
|
Definition
- At the second step, catalyzed by aspartate transcarbamoylase:
- Inhibited by CTP
|
|
|
Term
Chemical donors of pyrimidine ring atoms: [image] |
|
Definition
|
|
Term
| Carbamoyl Phosphate Synthetase II |
|
Definition
- carries out the first step in de novo synthesis of pyrimidines
- 2ATP + CO2 + Glutamine-->2ADP + Pi + Glutamate
- regulation is carried out here in mammals
- inhibited by UTP
- activated by ATP and PRPP
|
|
|
Term
| Aspartate Transcarbamoylase |
|
Definition
- carries out second step in de novo synthesis of pyrimidines
- Carbamoyl phosphate is converted to Carbamoyl aspartate by using an aspartate and releasing a phosphate
- regulation occurs here in prokaryotes
- inhibited by CTP
|
|
|
Term
|
Definition
Two reactions required for synthesis of UMP are catalyzed by a common protein (UMP synthase), involving different protein domains.
Genetic UMP synthase deficiency (rare) prevents UMP formation, resulting in: - growth abnormalities - megaloblastic anemia - urinary excretion of orotate
A diet rich in uridine improves the anemia and decreases orotate excretion. |
|
|
Term
| All pyrimidine nucleotides are derived from a _______ |
|
Definition
|
|
Term
|
Definition
By amination of UTP at C4 by CTP synthetase [image] |
|
|
Term
|
Definition
By methylation of dUMP is generated by methylation of dUMP at C5 by thymidylate synthase
|
|
|
Term
| Is pyrimidine salvage or purine salvage more crucial |
|
Definition
| Purine salvage is more crucial |
|
|
Term
| Degradation of pyrimidines differ from purine catabolism in two important ways |
|
Definition
- the pyrimidine ring is broken during degradation
- the end products of pyrimidine degradation are highly soluble
|
|
|
Term
|
Definition
an antitumor agent that is converted to 5-fluoro-dUMP, which inhibits thymidylate synthetase via irreversible binding (“suicide” inhibitor).
prevents formation of dTMP, thus limiting DNA synthesis in rapidly dividing cells. |
|
|
Term
|
Definition
Depletion of tetrahydrofolate inhibits dTMP production by limiting the supply of N5, N10-methylene-tetrahydrofolate. Thus, attenuation of cancer cell growth by methotrexate involves inhibition of both purine and pyrimidine biosynthesis. |
|
|
