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Post Midterm Biochem > Nucleotide metabolism > Flashcards

Nucleotide metabolism Flashcards

1
Q

Ribose phosphate pyrophosphokinase

A

ribose-5-phosphate+ATP–>5’-phosphoribosyl-1-pyrophosphate (PRPP)+AMP

requires Mg2+

PRPP used for de novo synthesis and salvage of purines and pyrimidines, synthesis of NAD+, histidine biosynthesis, and conversion of guanine to GMP

Activated by Pi

Inibited by Purine ribonucleotides (A/G/I M/D/T P)

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2
Q

Glutamine:phosphoribosyl pyrophosphate amidotransferase

A

PRPP (5’-phsophoribosyl-1-pyrophosphate) + Glutamine + H2O—>5’-phosphoribosylamine + Glutamate + PPi

Inhibitors: AMP, GMP, IMP

Activator: PRPP

First step of denovo purine synthesis; committed step; rate-limiting step

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3
Q

De Novo Purine synthesis

A

Constructing a purine ring on a preformed ribose-5-phosphate (as PRPP)

Overall uses 4 ATPs

Uses Aspartate, CO2, Glycine, Glutamine, N10-Formyl-tetrahydrofolate as sources of Carbons and Nitrogens

Tetrahydrofolate is especially important

End product is IMP

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4
Q

PABA analogues

A

aka Sulfonaminde/Sulfa drug

structural analoge of para-aminobezonic acid, an intermediate in bacterial synthesis of folic acid–>competitvely inhibits synthetic pathway (Dihdropeteroate synthetase)

Folic acid (N10-Formyl-tetrahydrofolate) is a required cofactor in purine synthesis so de novo purine synthesis is slowed in these bacteria.

Humans cannot synthesize folic acid, so purine synthesis is not affected

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5
Q

Folic Acid analogs

A

Including methotrexate and aminopterin (less common)

Inhibit reduction of dihydrofolate to tetraydrofolate catalyzed by dihydrofolate reductase

LImit amount of tetrahydorfolate (N10-Formyl-tetrahydrofolate) aroudn for purine synthesis thus slowing DNA replication

Used as an anti-cancer drug (toxic to all dividing cells), often used for leukemias

side effects: anemia, scaly skin, GI symptoms, respiratory tract disturbances, baldness

*Cancer cells can become resistant to MTX by amplification (duplication) of dihydrofolate reductase gene

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6
Q

Trimethoprim

A

Inhibits tetrahydrofolate synthesis in prokaryotes

Inhibits bacterial dihydrofolate reductase

used as prophalatic and for UTIs

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7
Q

Most common vitamin deficiency

A

Folic acid (B9)

-first seen as megaloblastic anemia–>Hb levels are low while blood marrow shows abnormally high number of megaloblastic cells (immature erythrocytes)

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8
Q

AMP synthesis

A

used to synthesize AMP from IMP, requires GTP

Adenylosuccinate Synthetase:
IMP + Aspartate + GTP—>Adenylosuccinate + GDP + Pi

Inhbited by AMP

Adenylosuccinase: Adenylosuccinate—>AMP + fumarate

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9
Q

Adenylosuccinate Synthetase:

A

Adenylosuccinate Synthetase:
IMP + Aspartate + GTP—>Adenylosuccinate + GDP + Pi

Inhbited by AMP

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10
Q

Adenylosuccinase

A

Adenylosuccinate—>AMP + fumarate

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11
Q

GMP synthesis

A

IMP dehydrogenase:
IMP + H2O + NAD+ ––>NADH + Xanthosine monophosphate (XMP)
inhibited by GMP and Mycophenolic Acid (deprives rapidly dviding B and T cells of nucleid acid components, used to prevent graft rejection)

GMP Synthetase:
XMP + ATP + Glutamine—>GMP + AMP + Glutamate

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12
Q

IMP dehydrogenase:

A

IMP + H2O + NAD+ ––>NADH + Xanthosine monophosphate (XMP)

inhibited by GMP and Mycophenolic Acid (deprives rapidly dviding B and T cells of nucleid acid components, used to prevent graft rejection)

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13
Q

Mycophenolic Acid

A

Mycophenolic Acid–>Inibits IMP dehydrogenase; deprives rapidly dviding B and T cells of nucleid acid components, used to prevent graft rejection

reversible, uncompetitive inhibitor

IMP + H2O + NAD+ ––>NADH + Xanthosine monophosphate (XMP)

also inhibited by GMP normally

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14
Q

GMP Synthetase:

A

GMP Synthetase:
XMP + ATP + Glutamine—>GMP + AMP + Glutamate

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15
Q

Purine Salvage:

A

2 enzymes:

Hypoxanthine-Guanine Phoshoribosyltransferase (HGPRT): Catalyzes 2 different rxns

Hypoxanthine + PRPP–>IMP + PPi
Guanine + PRPP–>GMP + PPi
(Lesch-Nyhan Syndrome)

Adenine Phosphoribosyltransferase (APRT)f

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16
Q

Lesch-Nyhan Dyndrome

A
  • X-linked recessive, near complete defciency of HGPRT
  • inability to salvage hypoxanthine and guanine
  • accumulation of uric acid (elevated in urine), end product of hypoxanthine and guanine degredation
  • Orange crystals (uric acid) in diaper
  • increased PRPP, decreased IMP and GMP; Increased de novo purine synthesis
  • symptoms include severe mental retardation, self-mutilation, ivoluntary movements, gout
17
Q

Degredation of Purines

A
  • Purines (and primidiens) are not essential components of the diet, most mononucleotides are synthesized de novo
  • most purines degraded to uric acid rather than salvaged
  • pyrimidies absorbed in intestinal mucosa dn returned to circulation (as are ribose and deoxyribose)
18
Q

Adenosice Deaminase (ADA)

A

Adenosine (nucleoSide) + H2O––>Inosine + NH3

Part of purine degredation (Inosine is a better substrate for purine nucleotide phosphorylase than adenosine)

Implicated in SCIDS

19
Q

SCIDs

A

Severe Combined Immunodeficiency

Deficiency of Adenosine Deaminase (ADA):
Adenosine–>Inosine

dATP accumulates in T-Cells and B-cells inhibiting DNA synthesis (inhibitor of Ribonucleotide reductase)

usually death before age 2 from infection

20
Q

Purine Nucleoside Phosphorylase

A

PNP or PNP(ase)

  • Prefers Inosine or guanosine as substrates but can act on andenosine
  • Purine nucleoside + Pi—>Purine + ribose-1-phosphate
  • deficieny causes T-cell related immunodeficiencies; decreased uric acid production; increased purine nucleosides and nucleotides
21
Q

Xanthine Oxidase

A

2 reactions:

Hypoxanthine + O2 + H2O –––> Xanthine + H2O2

Xanthine + O2 + H2O –––> Uric Acid + H2O2

Can be inhibited by allopurinol

22
Q

Gout

A
  • Hyperuricemia–caused most commonly by impaired elimination in urine but also by increased production due to errors in purine metabolism–leads to deposition of uric acid crystals in joints
  • Uric acid crystals lead to acute arthritic joint inflammation
  • Treated with Allopurinol: xanthine oxidase non-competitive inhibitor; accumulation and excretionof hypoxanthine and xanthine which are more soluble than uric acid
  • Colchicine-microtubule inhibitor; produces clinical improvement but does not decres serum uric acid; probably inhibits migrations of white cells to joints
  • 1° gout is genetic anf affects mainly males over 30
  • 2° gout brought on by disorders including leukemia, polycythemia, HGPRT deficiency treatment of cancer with antimetabolites, chronic renal insufficiency; affects men and women of any age
23
Q

Pyrimidine synthesis

A
  • pyrimidines synthesized before being attached to ribose-5-P (PRPP)
  • Rate-limiting/committed step is CPS-II (Mammals: Inhibited by UTP, activated by ATP; Prokaryotes: aspartate transcarbamoylase is regulated step, inhibited by CTP)
  • C’s and N’s come from Glutamine, Aspartic acid and CO2 (no folic acid derivatives)
  • Final product is UMP

Carbamoyl Phosphate synthetase II (CPS II)–>Aspartate transbarbamoylase–>dihydroorotase–>dihydroorotate dehydrogenase (uses NAD+)–>orotate phosphoribosyl-transferase–>OMP decarboxylase

24
Q

Carbamoyl Phosphate Synthetase II

A

2 ATP + CO2 + Glutamine—->Carbamoyl Phosphate + 2 ADP + 2 Pi + Glutamate

Mammals: Inhibited by UTP, activated by ATP

Prokaryotes:

25
Q

CPS I vs CPS II

A

CPS I vs II
•urea synthesis vs pyrimidine synthesis
•free NH3 vs glutamine for N source
•liver mitochondria vs cytosol of all nucleated cells
•activated by N-acetylglutamate vs is not affected
•no affect vs inhibited by UDP/UTP

26
Q

Orotic Aciduria

A
  • Deficiency in orotate phosphoribosyltransferase and OMP decarboxylase (2 domains of a single polypeptide)
  • abnormal growth, megaloblastic anemia, excretion of large amounts of orotic acid in urine
  • (also caused by deficiency of OTC ins urea cycle (type II hyperammonemia) as excess carbamoyl phosphate gets shunted through pyramidine synthesis)
  • rare genetic form can be treated with dietary uridine despite utilization of dietary nucleotides, enough is absorbed
  • aquired form may appear in patients being treated for cancer with pyrimidine analog
27
Q

UMP–>UTP

A

Uses NMP kinase and NDP kinase

28
Q

CTP Synthase

A

UTP + Glutamine + ATP—->CTP + Glutamate + ADP + Pi

29
Q

Ribonucleotide Diphosphate Reductase

A

converts adenosine, guanosine, cytosine, and uridine ribonucleotides to deoxyribonucleotides; Inhibited by dATP and hydroxyurea

NDP (except T) + Thioredoxin(2 S-H)—>dNDP + thioredoxin(S-S) + H2O

Thioredoxin reductase:
Thioredoxin(S-S; oxidized) + NADPH—>Thioredoxin(2 S-H; oxidized) + NADP+

Enzyme contains a single active site

2 activitiy sites may bind ATP (activates) or dATP (inhibits)

2 substrate specificity sites bind NTPs and increase conversion of different species of ribonucleotieds to maintain proper balance (ATP, dATP, dTTP, dGTP)

30
Q

Thymidylate synthase

A

dUMP——>dTMP
N5, N10-methylTHF
(B9)

indirectly inhibited by MTX (methotrexate)

Directly inhibited by 5-fluorouracil–>(5-FdUMP) in cancer treatments

31
Q

Purine and Pyrimidine analogs used in treatment of cancer

A
  • 5-fluorouracil: makes uracil analog; usually given with thymidine (protects normal, non-cancerous cells and cancer cells too kinda); converted to 5-fluorodeoxyridylic acid (dFUMP) which inhibits thymidilate synthase (affects cancer and non-cancer equally); in cancer cells 5-fluorocells is incorporated into RNA which is more detrimental to cancer cells than normal cells–>the RNA is what really gets them
  • bromodeoxyuridine: thymidine analog (large group)
  • trifluorothyidine: thymidine analog
  • AraC
32
Q

Degradation fo Pyrmidines

A
  • unlike purines, pyrimidines can be degraded to soluble precursors for other biomolecules
  • Can be salvaged by pyrimidine phosphoribosyltransferase (usese PRPP)

Post Midterm Biochem (16 decks)

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