Nitric oxide synthase isozymes

Schaefer U, Schneider A, Rixen D, Neugebauer E (1998) Neutrophil adhesion to histamine stimulated cultured endothelial cells is primarily mediated via activation of phospholipase C and nitric oxide synthase isozymes. Inflamm Res 47(6) 256-264 Schaefer U, Schmitz V, Schneider A, Neugebauer E (1999) Histamine induced homologous and heterologous regulation of histamine receptor subtype mRNA expression in cultured endothelial ceUs. Shock 12(4) 309-315... 

U. Fostermann, E. 1. Closs, J. S. Pollock, M. Nakane, P. Schwarz, 1. Gath and H. Kleinert, Nitric Oxide Synthase Isozymes Characterization. Purification. Molecular Cloning, and Functions. Hypertension 23 (1994) 1121-1131. 

Forstermann, U., Gloss, E. I., Pollock, J. S., Nakane, M., Schwarz, P., Gath, I., and Kleinert, H. (1994). Nitric oxide synthase isozymes Characterization, molecular cloning and functions. Hypertension 23, 1121-1131. 

Ji, H.T., Stanton, B.Z., Igarashi, J., Li, H.Y., Martasek, P., Roman, L.J., Poulos, T.L., Silverman, R.B. Minimal pharmacophoric elements and fragment hopping, an approach directed at molecular diversity and isozyme selectivity. Design of selective neuronal nitric oxide synthase inhibitors. J. Am. Chem. Soc. 2008, 130, 3900-14. 

In some instances the type of inhibition has been found to be isozyme specific. For example, inducibly expressed isozymes (iNOS) and constitutively expressed isozymes (cNOS) of nitric oxide synthase (NOS) all catalyze the conversion of L-arginine to L-citrulline and nitric oxide (Equation 17.34). 

Garcin ED, Bruns CM, Lloyd SJ, Hosfield DJ, Tiso M, Gachhui R, Stuehr DJ, Tainer JA, Getzofif ED (2004) Structural basis for isozyme-specific regulation of electron transfer in nitric-oxide synthase. J Biol Chem 279 37918-37927... 

Fig. 17.5 Effect of nitric oxide on the synthesis of methionine and S-adenosylmethionine and methylation reactions. NO inhibits methyltetrahydrofolate reductase (MTR). This results in a decrease in tetrahydrofolate (FH4) and methionine. Additional reduction in the FH4 level may occur by the NO-induced oxidation of ferritin, a compound that inhibits the proteasomal degradation of FH4. NO affects SAM synthesis not only by inducing a decrease in methionine synthesis but also by directly inhibiting the liver-specific methyl-thioadenosyltransferase I/III (MATI/III) isozymes. The fall in SAM level cannot be fully compensated by an increase in the extrahepatic isozyme MATH, since this enzyme is inhibited by its reaction product. The reduction in homocysteine utilization for methionine synthesis may result in homocysteine accumulation. This probably does not lead to a consistent rise in cystathionine and reduced glutathione synthesis, dne to a reduced stabilization of cystathionine P-synthase (CBS) by SAM. Consequently, an inciea.se in SAH, associated with a decrease in the SAM/SAH ratio, inhibits methyltransferases (MT) and DNA methylation. The reduction in SAM level may decrease IicBa activation, thus favoring NF-kB activity...

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