Abstract | This chapter surveys the roles of pterins in biology and provides an understanding of biochemical pathways that determine tetrahydrobiopterin (BH4) levels in mammalian cells and how they are regulated. Nitric oxide synthases (NOSs) are the most recent addition to a group of enzymes, now totaling five, that rely on the naturally occurring cofactor for catalytic activity. BH4 is a pteridine, a chemical classification defined by a unique heterocyclic ring structure. Diverse mechanisms regulate BH4 expression and, accordingly, serve as verified or potential control points for modulating NOS function in physiology and pathophysiology. Included in the group of BH4-dependent enzymes are three aromatic amino acid hydroxylases, where a redox function of BH4 in catalysis is well established. Despite the absolute dependence of NOS on BH4 for catalytic function, the mechanism by which BH4 functions in NO synthesis is arguably the most poorly understood aspect of NOS enzymology. One certain conclusion is that NOS uses BH4 in a manner that differs from all other known BH4-dependent enzymes. Evidence is presented to support the view that BH4 availability is a major determinant of mammalian NO-synthesis rate in physiological and pathophysiological settings. |
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