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J Biol Chem, Vol. 274, Issue 21, 14692-14698, May 21, 1999
From the Department of Pharmaceutical Chemistry, University of
California, San Francisco, California 94143-0446
The primary sequences of the three mammalian
nitric- oxide synthase (NOS) isoforms differ by the insertion of a
52-55-amino acid loop into the reductase domains of the endothelial
(eNOS) and neuronal (nNOS), but not inducible (iNOS). On the basis of studies of peptide derivatives as inhibitors of ·NO formation
and calmodulin (CaM) binding (Salerno, J. C., Harris, D. E.,
Irizarry, K., Patel, B., Morales, A. J., Smith, S. M., Martasek, P., Roman, L. J., Masters, B. S., Jones, C. L., Weissman, B. A., Lane, P., Liu, Q., and Gross, S. S. (1997) J. Biol. Chem. 272, 29769-29777), the insert
has been proposed to be an autoinhibitory element. We have examined the
role of the insert in its native protein context by deleting the insert
from both wild-type eNOS and from chimeras obtained by swapping the
reductase domains of the three NOS isoforms. The Ca2+
concentrations required to activate the enzymes decrease significantly when the insert is deleted, consistent with suppression of
autoinhibition. Furthermore, removal of the insert greatly enhances the
maximal activity of wild-type eNOS, the least active of the three
isoforms. Despite the correlation between reductase and overall
enzymatic activity for the wild-type and chimeric NOS proteins, the
loop-free eNOS still requires CaM to synthesize ·NO. However,
the reductive activity of the CaM-free, loop-deleted eNOS is enhanced
significantly over that of CaM-free wild-type eNOS and approaches the
same level as that of CaM-bound wild-type eNOS. Thus, the inhibitory
effect of the loop on both the eNOS reductase and
·NO-synthesizing activities may have an origin distinct from the loop's inhibitory effects on the binding of CaM and the concomitant activation of the reductase and ·NO-synthesizing activities. The
eNOS insert not only inhibits activation of the enzyme by CaM but also
contributes to the relatively low overall activity of this NOS isoform.
Autoinhibition of Endothelial Nitric-oxide Synthase
IDENTIFICATION OF AN ELECTRON TRANSFER CONTROL ELEMENT
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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