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Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions
U Förstermann1, E I Closs, J S Pollock
1Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany.
Hypertension (Dallas, Tex. : 1979)
|June 1, 1994
Summary
Three nitric oxide (NO) synthase isozymes (I, II, and III) exist, each with distinct gene locations, functions, and regulation. These enzymes are crucial in various physiological and pathological processes, from neuronal signaling to immune responses.
Area of Science:
- Biochemistry and Molecular Biology
- Physiology
- Genetics
Background:
- Nitric oxide (NO) synthase (NOS) enzymes catalyze NO production, a critical signaling molecule.
- Three human NOS isozymes (NOS I, NOS II, NOS III) have been identified, each encoded by a distinct gene.
- These isozymes exhibit differential tissue distribution, regulation, and functional roles.
Purpose of the Study:
- To provide a comprehensive overview of the three human nitric oxide synthase isozymes.
- To detail their genetic basis, molecular characteristics, and functional significance.
- To highlight their roles in diverse physiological and pathological conditions.
Main Methods:
- cDNA isolation and sequencing
- Amino acid sequence analysis and comparison across species
- Review of existing literature on NOS isozyme expression and function
Main Results:
- Human NOS isozymes I, II, and III are encoded by genes on chromosomes 12, 17, and 7, respectively.
- Amino acid sequences show limited identity (<59%) among human isozymes but high conservation across species (>80%).
- All isoforms utilize L-arginine and molecular oxygen, requiring cofactors like NADPH and tetrahydrobiopterin, and bind calmodulin and heme.
Conclusions:
- Isoform I, constitutively expressed in neurons and epithelial cells, is Ca2+/calmodulin-dependent and regulates synaptic transmission, blood pressure, and smooth muscle relaxation.
- Isoform II, inducible by cytokines, is Ca2+-independent and produces large NO amounts, implicated in host defense against parasites and in autoimmune diseases and septic shock.
- Isoform III, primarily in endothelial cells, is constitutively expressed and Ca2+/calmodulin-regulated, maintaining vascular tone, preventing platelet adhesion, and inhibiting smooth muscle proliferation.