PubMed · 8236437
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B T Kaufman. 1993. Why NADP?. https://doi.org/10.1016/0968-0004(93)90033-j
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Tyrosine hydroxylase (TH) is the initial and rate-limiting enzyme in the biosynthesis of the neurotransmitter dopamine (DA). TH activity is inhibited by peroxynitrite (ONOO(-)) by a mechanism that involves nitration of tyrosine residues and oxidation of cysteine residues in the enzyme. Reduced forms of the nicotinamide adenine dinucleotide cofactors, NADH and NADPH, protect TH from inhibition by ONOO(-) and prevent nitration of tyrosine residues. NAD, the oxidized form of the cofactors, neither protects TH from ONOO(-)-induced inhibition nor prevents the nitration of tyrosine residues in the enzyme. These results suggest that the redox status of the nicotinamide nucleotide cofactors could influence the ability of ONOO(-) to modify proteins that are important to the function of DA neurons.
Bacteria readily transform 2,4,6-trinitrotoluene (TNT), a contaminant frequently found at military bases and munitions production facilities, by reduction of the nitro group substituents. In this work, the kinetics of nitroreduction were investigated by using a model nitroreductase, NAD(P)H:flavin mononucleotide (FMN) oxidoreductase. Under mediation by NAD(P)H:FMN oxidoreductase, TNT rapidly reacted with NADH to form 2-hydroxylamino-4,6-dinitrotoluene and 4-hydroxylamino-2,6-dinitrotoluene, whereas 2-amino-4,6-dinitrotoluene and 4-amino-2,6-dinitrotoluene were not produced. Progressive loss of activity was observed during TNT reduction, indicating inactivation of the enzyme during transformation. It is likely that a nitrosodinitrotoluene intermediate reacted with the NAD(P)H:FMN oxidoreductase, leading to enzyme inactivation. A half-maximum constant with respect to NADH, K(N), of 394 microM was measured, indicating possible NADH limitation under typical cellular conditions. A mathematical model that describes the inactivation process and NADH limitation provided a good fit to TNT reduction profiles. This work represents the first step in developing a comprehensive enzyme level understanding of nitroarene biotransformation.
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