• Nucleotide base
• 2 rings (6 and 5 member ring)
• A,G, Xanthine and Hypoxanthine
• 9 atom heterocycle (4N, 5C)

• Nucleotide base
• 1 ring (6 member ring)
• C,T,U and Orotic Acid
• 6 atom heterocycle (2N, 4C)

• You start with the six member ring. #1 goes to the N closest to the functional group (CO(G) or NH₂(A))
• You go around the ring so that the next N has the lowest # that is possible.
• N7 in the other ring is always closest to the functional group.

• The N opposite the functional group gets #1.
• You then go around so the next N has the lowest # possible.

• Base + pentose sugar
• ends in (ine)

First step: 

Ribose 5-P→ PRPP (PRPP synthetase)

(-)AMP, IMP, GMP

PRPP→ PRA (transferase)

(-) AMP, IMP, GMP (feedback inhibition)

(+)PRPP(can overcome inhibition)

• N1 Aspartate
• N3, N9 Glutamine
• C2, C8 Formyl-THF
• C4, C5, N7 Glycine
• C6 CO₂

• Anitbiotics
• Anticancer drugs
• Azaserine: Glutamine antagonist. Inhibits steps in which glutamine donates a N.
• Methotrexate:(folic acid analog) Inhibites reduction of Dihydrofolate→ THF by limiting the amount of THF available for use in purine sythesis

• Its a coenzyme thats involved in the tranfser of single carbon groups.
• Plays a role in Purine/Pyrimadine synthesis and amino acid conversions.
• If deficient, actively dividing or growing cells are the first affected.

• Nucleic Acid production
• Carriers of activated intermediates in carbohydrate, lipid, and protein synthesis.
• Structural component of coenzymes
• Energy source
• Metabolism

Base= Hypoxanthine

Nucleoside: Inosine

Nucleotide: Inosinate

It is a common precursor of AMP, GMP, ATP, GTP

• ADP and GDP
• The first reaction in each pathway is inhibited by the end product.

IMP→ GMP (ATP)

IMP→ AMP (GTP)

Both are irreversible

APRT

HGPRT (deficiency leads to Lesch-Nylan Syndrome)

• HGPRT deficiency
• X-linked recessive trait(mostly males get it)
• Increased PRPP and De Novo Purine synthesis
• Excessive uric acid production(Hyperuricemia)
• Self Mutilation
• Involuntary Movements
• Neurological defects
• Mental Retardation
• Hyperuricemia

• degraded to Xanthine which is precursor for Uric Acid synthesis.

Purine Metabolism Disorder

• Severe combined immunodificiency (SCID)
• dATP build up which inhibits DNA synthesis.
• Children with it usually die before 2 from severe infections.

Purine Metobolism disorder

• causes T cell dysfunction
• decrease in Uric Acid production
• increased levels of nucleosides and nucleotides.
• dGTP buildup

Allopurinol

• treatment of accumulation of uric acid crystals. Gout(also called hyperuricemia)
• Inhibits Xanthine Oxidase.

• Anti-inflammatory drugs: releaves pain
• Uricosuric agents: increase renal excretion of uric acid
• Inhibition of xanthine oxidase: decrease formation of uric acid.
• Changes in diet: low protein diet. excess of amino acids increases de novo purine synthesis.

• Pyrimidines are not synthesized as nucleotides.
• Pyrimidine ring is completed before Ribose 5-P is added.

• C2, N3 Carbamyol-P (derived from glutamine and CO₂)
• N1, C4,5,6 Aspartate

First step

• Glutamine + 2ATP + CO₂→ Carbamoyl Phosphate (CP)
• enzyme: CPS II
• cytosolic
• (-)UTP, CTP
• (+) ATP, PRPP

Step 2

• Carbamoyl Phosphate(CP)→ Carbamoyl Aspartate
• enzyme: Aspartate Transcarbamoylase

• Bifunctional enzyme deficiency. (Pyrimidine synthesis)
• Results in Ortic acid in the blood and urine.
• Growth stunt. Megaloblastic anemia and leukopenia are clinical signs.
• Mild form leads to accumulation of carbamoyl phosphate in the liver mitochondria.
• Can be treated orally with uridine(UMP) and/or cytidine.

• the disease stops UMP production
• UMP is converted to UTP.
• UTP provides negative feedback to CPS II which is the rate limiting step of Pyrimidine synthesis.
• That stops the production of Orotate

• converts NDP to dNDP
• necessary for DNA synthesis to occur
• controled by negative feedback mechanisms.
• Thioredoxin is coenzyme

• ATP activates RR
• is dATP binds here it will prevent reduction of all four nucleoside diphosphates.
• contains active and allosteric sites.

• Binding of certain nucleoside triphosphates (ATP, dATP, dTTP, or dGTP) regulates substrate specificity.
• Whatever is needed for DNA synthesis will be used.

• converts dUMP to TMP
• dihyrofolate reductase has something to do with it too.

5- fluorouracil

• Antineoplastic(Cancer) drug
• Inhibits Thymidylate Synthetase
• Thymine analog

• Antineoplastic(Cancer) drugs
• Inhibits Dihydrfolate Reductase
• Folate analog

Antineoplastic(CAncer) drug

Inhibits:

Adenylosuccinate Synthase: IMP→AMP

IMP Dehydrogenase: IMP→GMP

PRPP Amidotransferase(Purine synthesis):

Can also be incoporated into nucleotides and promote defective amino acids.

• Pyrimidine degredation. Thats why there are few disorders associated with pyrimidine metabolism.
• purine degrades into insoluble uric acid

Pur:Synthesized on PRPP

Pyrim: Synthesized then added to PRPP

Pur: Regulated by GTP/ATP

Pyrim: Regulated by UTP

Pur: Generates IMP

Pyrim: Generates UMP/CMP

Pur: Successive addition of atoms

Pyrim: Synthesized from two common metabolic intermediates.

Pur: Ribose 5-P serves as base for addition of atoms

Pyrim: Nucleotides are made prior to linkage with Ribose 5-P