nucleic acid metabolism lecture nam01

Nucleic Acid MetabolismPurine AnabolismIMP Pathway

Dr. Aga Syed SameerCSIR Lecturer (Tutor)

Department of Biochemistry,

Medical College,

Sher-I-Kashmir Institute of Medical Sciences,

Bemina, Srinagar, Kashmir, 190018. India.

Nucleic Acid Metabolism

• Nucleotides• Essential for all cells• Carriers of activated intermediates in carbohydrate, lipids

and proteins• CoA• FAD• NAD• NADP

• Energy Carriers• ATP

• Inhibiting or activating enzymes• DNA• RNA

Nucleotide Structure

• Ribose Sugar• Ribose

• Deoxyribose

• Base• Purines

• Pyrimidines

• Nucleoside• Base plus sugar

• Nucleotide• E.g., AMP, ADP, ATP

Nomenclature

• DNA Purine Bases• Adenine• Guanine

• Purine Nucleosides• Adenosine • Guanosine

• DNA Nucleotides (Purine)• dAMP (deoxyadenylate)• dGMP (deoxyguanylate)

• RNA Nucleotides (Purine)• Adenylate (AMP)• Guanylate (GMP)

Nomenclature

• DNA Pyrimidine Bases• Thymine• Cytosine (Also RNA)

• DNA Pyrimidine Nucelosides• Thymidine• Cytidine

• DNA Pyrimidine Nucleotides• (dTMP) deoxythymidylate• (dCMP) deoxycytidylate

• RNA Pyrimidine Nucleotides• (CMP) cytidylate• (UMP) uridylate

Biosynthesis•Two ways by which nucleotides can be synthesized

•Denovo Pathway

•Salvage Pathway

•Denovo synthesis of nucleotides begins with their metabolic

precursors: Amino Acids; R5P; CO2; NH3

•Salvage Pathway recycles the free bases and nucleosides

released from nucleic acid breakdown

PRPP 5-Phosphoribosyl 1-Pyrophosphate

•Activation of the ribose sugar component

•HMP

•ATP Required

•Mg2+

•Pi activates and nucleosides inhibit

Purine Biosynthesis• IMP (Inosine Monophosphate)

• Precursor to• GMP and AMP

• Utilizes (Substrates)• One Glycine

• NH3 of Glutamine

• Folate (N10-formyl-THF)

• CO2

• ATP’s (Six : Till IMP Synthesis)

• Mg2+, K+, Mn2+

• (Aspartate) + GTP {AMP Synthesis}

• NH3 of Glutamine + ATP (2 Equivalent) {GMP Synthesis}

IMP Pathway

IMP Pathway

IMP Pathway

IMP Pathway

IMP Pathway

IMP Pathway

IMP Pathway

IMP Pathway

• Utilizes (Substrates)• One Glycine

• NH3 of Glutamine

• NH3 of Aspartate

• Formyl of Folate (N10-formyl-THF)

• CO2

• ATP’s (Six : Till IMP Synthesis)

• Mg2+, K+, Mn2+

IMP Pathway

IMP to AMP and GMP

• AMP production

• Aspartate

• GTP

• GMP production

• Glutamine

• NAD

• ATP (Equivalent to two)

AMP and GMP Pathway

Regulation

• Four major feedback mechanisms cooperate in regulating the overall rate of de novo purine nucleotide synthesis and the relative rates of formation of the two end products, adenylate and guanylate

• First is the transfer of an amino group to PRPP to form5-phosphoribosylamine by glutamine-PRPP amidotransferase

• Inhibited by the end products IMP, AMP, and GMP

• AMP and GMP act synergistically in this concerted inhibition

Regulation

• Second control by an excess of GMP in the cell inhibits formation of xanthylate from inosinate by IMP dehydrogenase, without affecting the formation of AMP. And also, Adenylate inhibits formation of adenylosuccinate by adenylosuccinate synthetase, without affecting the biosynthesis of GMP

• Third a reciprocal arrangement between ATP/GTP that tends to balance the synthesis of the two ribonucleotides

• Fourth and the final control mechanism is the inhibition of PRPP synthesis by the allosteric regulation of ribose phosphate pyrophosphokinase by ADP and GDP

Regulation

• PRPP amidotransferase is rate limiting• Inhibited by AMP and GMP

Salvage Pathway

Hypoxanthine

Guanine

Adenine

PRPP

IMP

GMP

AMP

PPi

HGPRTase

AGPRTase

Kinases for Interconversion

AMP

+

GMP

ATP

2ADP

GDP + ADP

Adenylate Kinase

Guanylate Kinase

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