nucleotide.txt

Pyrimidine de novo pathway enzyme

2 ATP + CO2 + Gln --> Carbamoyl Phosphate

UTP inhibits

Pyrimidine de novo pathway enzyme

CARBAMOYL PHOSPHATE + ASP --> CARBAMOYL ASPARTATE

Pyrimidine de novo pathway

OROTATE + PRPP --> OROTIDINE 5'-MONOPHOSPHATE (OMP)

Part of a protein with 2 active enzymatic properties, including OMP DECARBOXYLASE

OROTINE ACIDURIA: Block in UTP & CTP production

Pyrimidine de novo pathway enzyme

OROTIDINE 5'-MONOPHOSPHATE (OMP) --> URIDINE 5'-MONOPHOSPHATE (UMP)

Ihibited by UMP, CMP

Pyrimidine de novo pathway enzyme

UTP + GLUTAMINE --> CTP

Inhibited by CTP

Important enzyme linking sugar to nucleotide metabolism

RIBOSE 5-PHOSPHATE + ATP --> 5-PHOSPHORIBOSYL-1-PYROPHOSPHATE

Brain and bone marrow have NO de novo pathway

Rely on salvage pathway

Pyrimidine salvage pathway enzyme

PYRIMIDINE BASE + PRPP --> PYRIMIDINE 5'-MONOPHOSPHATE

Purine ring is built piece-meal onto the ribose 5'-phosphate, whereas pyrimidine built THEN added to ribose 5'-phosphate after completion

First enzyme in Purine de novo pathway

PRPP --> 5-phosphoribosylamine

IMP, AMP, GMP inhibits: ALL MUST BE PRESENT

PRPP upregulates PRPP Synthetase

Purine salvage pathway enzyme

HYPOXANTHINE OR GUANINE + PRPP --> IMP OR GMP + PPi

GOUT: Deficiency leads to increase in free purines; leads to increased uric acid production

PRPP increases leading to upregulated de novo synthesis; leads to increased uric acid production

Purine salvage pathway enzyme

ADENINE + PRPP --> AMP + PPi

Important intermediate in purine de novo synthesis

ATP required for GMP synthesis; GTP required for AMP synthesis

Converts ribonucleoSIDES to deoxyribonucleosides

Ribonucleosides MUST be in Diphosphate form (ADP, GDP, CDP, UDP)

dATP and dGTP inhibit

Synthesis of deoxythymidine monophosphate

dUDP + METHYLENE THF --> dTDP + DHF

THF must be regenerated by DIHYDROFOLATE REDUCTASE

Key enzyme in deoxyribonucleoside conversion

OXIDIZED THIOREDOXIN --> REDUCED THIOREDOXIN

Degrades purines

AMP --> HYPOXANTHINE

Leads to increase in uric acid production

Final enzyme in purine degredation pathway that produces uric acid

HYPOXANTHINE --> XANTHINE --> URIC ACID

Allopurinol inhibits: think GOUT; Hyperuricemia

Acute arthritic inflammatory attacks in joints, causing pain and destruction of connective tissue

Uric acid stones in kidney, causing nephropathy

focal urate deposits that are visible (tophi)

Rapid tissue turnover (cancer)

Purine rich diet

High PRPP SYNTHASE activity leading to upregulated de novo pathway --> uric acid

Low HGPRT activity leads to less salvaging of purine bases, which get degraded into uric acid

High PRPP leads to increased de novo pathway --> uric acid

Low IMP and GMP from salvage pathway --> less feedback inhibition of de novo pathway --> uric acid

COLCHICINE: pain from acute attack, swelling, inflammation

PROBENECIDE: increases uric acid excretion from kidneys, works only if renal excretion is low

ALLOPURINOL: inhibits XO, leads to increased hypoxanthine/xanthine which is very soluble

Mental retardation

Severe plasticity

Severe self-mutilation

Hyperuricemia -- associated with high morbidity/mortality

Complete deficiency in HGPRT

Deficient dopaminergic neurons -- purines required for synthesis of neurotransmitters

Can use Allopurinol to treat

Loss of immune response due to loss of T/B lymphocytes (lymphocytopenia)

Decreased circulating immunoglobulins

Chronic infection

Low ADA leading to increased adenosine and deoxyadenosine

Low ribonucleotide reductase --> increased nucleosides which are toxic to lymphocytes, inhibition of DNA synthesis

Isolation

Blood transfusion

Bone marrow transplant

Enzyme replacement therapy

Gene therapy

Severe anemia

Accumulation of orotate or orotidine in serum and excretion of orotate in urine

Immunodeficiency

Poor postnatal growth

Pyrimidine biosynthesis deficit

Deficient orotate phosphoribosyl transferase and/or orotidylate decarboxylase --> block in UTP and CTP production

Give uridine or Cytidine (nucleoSIDES) --> inhibits carbamoyl phosphate synthetase II which lowers de novo orotate and improves anemia

Anti-cancer drug

inhibits thymidylate synthesis

slows DNA replication

Anti-cancer drug

Inhibits ribonucleatide reductase

slows DNA replication

Anti-cancer drug

Inhibits de novo purine biosynthesis

Slows DNA replication

Anti-cancer drug

Inhibits dihydrofolate reductase

Slows DNA replication

Prevents graft rejection (purine inhibitor)

inhibits inosine monophosphate dehydrogenase in rapidly proliferating T/B cells

Sulfonamides target bacteria

Inhibit folic acid synthesis and thus purine synthesis

5-FLUOROURACIL (5-FU)


INHIBITS PRODUCTION OF dTDP

HYDROXYUREA (HU)

6-MERCAPTOPURINE

METHOTREXATE (MTX)

INHIBITS dTDP SPECIFICALLY