Nucleotide Metabolism - Roth 3/14/16 Flashcards

Question

uric acid gout

Answer 1

uric acid is close to solubility limit in serum pH and temp can affect solubility buildup of uric acid → deposition of monosodium urate crystals in tissues: **GOUT** _primary hyperuricemia_: error in uric acid metab * overactive PRPP synthetase * dereg of PRPP-amino-transferase * Lesch Nyhan syndrome _secondary hyperuricemia_ * malignancy (elevated cell turnover) * chronic renal insufficiency (underexcretion - most common cause of gout) * G6Pase def (von Gierke disease; increased G6P stimulates PRPP production) * meds like HCTZ _symptoms_: joint pain, swelling, warmth, redness, tenderness in joints _tx_: **allopurinol** : analog of hypoxanthine, **inhibits xanthine oxidase** * competitive inhibitor of xanthine oxidase * xanthine oxidase converts it into alloxanthine : potentnt irreversible inhibitor of enzyme * buildup of hypoxanthine → salvaged to produce IMP * IMP is an inhibitor of PRPP-amino-transferase (de novo purine synth) → less purine synth, less degradation! **febuxostat,** non-purine analog that also **inhibits** **xanthine oxidase**

Answer 2

urate in serum is also an antioxidant → scavenges ROS

Answer 3

purine nucleotide cycle links nucleotide metabolism to TCA cycle via fumarate (generated during IMP → adenylosuccinate → AMP + fumarate → IMP) * indirectly replenishes an intermediate of the TCA cycle = anaplerotic rxn during sustained muscle activity, TCA cycle intermeds need to be replenished for energy production * in muscle cells, purine nt cycle can do this by replenishing fumarate; 3 enzymes involved are upreg'd in muscle cells

Answer 4

_remember_: NOT SYNTHESIZING parent base ON the PRPP backgone (de novo purine synth)... * parent base synthesized entirely * parent base attached to PRPP _1. synthesizing carbamoyl phosphate_ (regulated step of pyrimidine synth) 2ATP + CO2 + Gln → carbamoyl phosphate * carbamoyl phosphate synthetase II (cytosolic **CPS II**; distinct from CPS I, mitochondrial rate limiting step in urea synth, protein metab!!!!) * + : ATP, PRPP * - : UTP _2. competing pyrimidine ring and ring closure_ carbamoyl P (2 C) + 4 Asp → orotate (ringed, 6C) * rxn is coordinated by **CAD** - large polypep including 3 separate catalytic domains (**CPS II**, Asp-adding enzyme, ring-closing enzyme) * one addt'l rxn occurs on outer surface of inner mito mem _3a. attaching pyrimidine base to ribophosphate backbone_ orotate + PRPP → ortidylate (OMP - precursor to UMP) [**orotate phosphoribosyl transferase**] _3b. converting OMP to UMP_ (parent pyrimidine) OMP (ortidylate) → UMP (uridylate) [**orotidylate decarboxylase**] \* **orotate phosphoribosyl transferase** and **orotidylate decarboxylase** are diff members of same polypepide * decreased activity of either = _orotic aciduria_ (megaloblastic anemia, lots of orotate in urine) * _tx_: supplementation with CMP, UMP, uridine to bypass metabolic block _4. synthesizing UDP and UTP_ UMP → UDP → UTP via phosphorylation * requires specific **nucleoside monophosphate kinase**, nonspecific **nucleoside diphosphate kinase** _5. synthesizing CTP_ \*only way to make cytosine nt: convert UTP + ATP + Gln→ CTP [**CTP synthetase**] * CTP inhibits **CTP synthetase** via feedback inhibition \*\*\*only ways to make thymine nt: 1. from precursor, deoxyuridine monophosphate (dUMP) 2. by deaminating deoxycytidine monophosphate (dCMP) _detour_: convert ribonucleotides to deoxyribonucleotides

Answer 5

deficiency in activity of enzymes involved in synthesizing OMP, converting OMP → UMP in pyrimidine synth \***orotate phosphoribosyl transferase** and **orotidylate decarboxylase** are diff members of same polypepide * decreased activity of either = _orotic aciduria_ _symptoms_: megaloblastic anemia, lots of orotate in urine _tx_: supplementation with CMP, UMP, uridine to bypass metabolic block

Answer 6

need dUMP or dCMP for thymine synthesis nucleoside diphosphates (ADP, GDP, CDP, UDP) → deoxynucleotide diphosphates (dADP, dGDP, dCDP, dUDP) * **ribonucleotide reductase**, highly expressed in proliferating cells that enter S phase * requires NADPH to keep catalytic site reduced _regulation_ + : binding of ATP to active site - : binding of dATP to active site (feedback inhibition? **which molecule binds to active site (i.e. which molecule the enzyme is reducing at a given time)** is regulated by binding of other molecules to _substrate specificity site_ _in ADA deficiency..._ lack of ADA → buildup of adenosine → conversion to ribont, deoxyribont forms : high levels of dATP * inhibits ribonucleotide reductase → blocks production of all deoxyribonucleotides → prevents bone marrow from making B and T cells :(

Answer 7

_in ADA deficiency..._ * lack of ADA → buildup of adenosine → conversion to ribont, deoxyribont forms : high levels of dATP * inhibits **ribonucleotide reductase** → blocks production of all deoxyribonucleotides → prevents bone marrow from making B and T cells :(

Answer 8

requires dUMP, formed by either... * deamination fo dCMP (main pathway) * phosphorylase action on dUTP (gets rid of excess dUTP - prevents it from getting incorp'd into DNA, where it doesnt belong) dUMP +N5N10-methylene THF → dTMP [**thymidylate synthase**] * antitumor agent _5-fluorouracil_ gets converted to 5-FdUMP - covalent inhibitor of **thymidylate synthase**, leading to lack of thymine and cell death * _methotrexate_ and others inhibit DHFR → prevent recycle THF, block purine and TMP synthesis

Answer 9

purine salvage: enzymes link PRPP to base → ribonucleotides (1 step) _pyrimidine salvage requires 2 steps_ *1. base coupled to sugar* pyrimidine base + ribose-1P → pyrimidine nucleoside + P [**nucleoside phosphorylase**] *2. addition of P to nucleoside* pyrimidine nucleoside + ATP → pyrimidine nucleotide + ADP [**nucleoside kinase**] * need to know **thymidine kinase** : salvages nucleoside thymidine → TMP]

Answer 10

guanosine analog interferes with viral replication * P'd by viral thymidine kinase → preferentially incorporated into viral DNA → premature DNa chain termination

Answer 11

don't need to know details catabolism of pyrimidines → highly soluble products CMP, UMP → beta-alanine TMP → beta-aminoisobutyrate NH3 and CO2 released in process

Nucleotide Metabolism - Roth 3/14/16 Flashcards

(35 cards)