Q. Describe de novo biosynthesis of Inosine monophosphate (IMP). How will you form dUDP from it? [no 2, 2015/16]
Introduction
Nucleotides, composed of nucleosides, a sugar moiety, and one or more phosphate groups, are essential for fundamental biochemical functions and overall physiological well-being. The synthesis of nucleotides primarily occurs in the liver, with the brain also contributing to a lesser extent.
The Two Phases of Nucleotide Biosynthesis
The process of nucleotide biosynthesis can be divided into two key phases:
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Uncommitted Stage: This stage involves the formation of phosphoribosyl pyrophosphate (PRPP). It is referred to as "uncommitted" because PRPP serves as a precursor for various metabolic pathways, not just nucleotide synthesis.
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Committed Steps: This phase encompasses the specific reactions leading to the formation of inosine monophosphate (IMP), a crucial precursor for both purine and pyrimidine nucleotides.
Formation of PRPP
The synthesis of PRPP is the first step in nucleotide biosynthesis:
Ribose 5-phosphate + ATP → Phosphoribosylphosphate (PPRP) + AMP
Enzyme: PRPP synthase
Regulation of Nucleotide Biosynthesis
The regulation of nucleotide biosynthesis is complex and involves multiple levels of control:
- Step 1 – Amidophosphoribosyltransferase: This enzyme catalyzes the first committed step in purine biosynthesis and is inhibited by AMP and GMP, illustrating feedback inhibition.
- Adenylsuccinic Synthetase and IMP Dehydrogenase: These enzymes are also inhibited by AMP and GMP, further regulating purine nucleotide levels.
- Availability of PRPP: The synthesis of PRPP is regulated by negative feedback from purine and pyrimidine nucleotides, ensuring balanced production.
- Salvage Pathway: The salvage pathway, which recycles preformed purine and pyrimidine bases, influences de novo synthesis by modulating PRPP availability and providing inhibitory nucleotides.
Energetics of IMP Synthesis
The de novo synthesis of IMP is an energy-demanding process:
- 5 ATP molecules are required to form one molecule of IMP.
- 1 GTP molecule is needed to form AMP from IMP.
- 4 ATP molecules are required to form GMP from IMP.
Biomedical Importance of Nucleotides
Nucleotides play critical roles in various biological processes:
- Building Blocks of Genetic Material: Nucleotides are the fundamental units of DNA and RNA, essential for storing and transmitting genetic information.
- Energy Carriers: Nucleoside triphosphates, particularly ATP, serve as the primary energy currency of the cell, powering countless cellular processes.
Clinical Significance
Disruptions in nucleotide metabolism can lead to various clinical conditions, highlighting their importance in human health.
