Nitric oxide synthases reveal a role for calmodulin in controlling electron transfer.

HM Abu-Soud, DJ Stuehr - Proceedings of the National …, 1993 - National Acad Sciences
Proceedings of the National Academy of Sciences, 1993National Acad Sciences
Nitric oxide (NO) is synthesized within the immune, vascular, and nervous systems, where it
acts as a wide-ranging mediator of mammalian physiology. The NO synthases (EC 1.14.
13.39) isolated from neurons or endothelium are calmodulin dependent. Calmodulin binds
reversibly to neuronal NO synthase in response to elevated Ca2+, triggering its NO
production by an unknown mechanism. Here we show that calmodulin binding allows
NADPH-derived electrons to pass onto the heme group of neuronal NO synthase …
Nitric oxide (NO) is synthesized within the immune, vascular, and nervous systems, where it acts as a wide-ranging mediator of mammalian physiology. The NO synthases (EC 1.14.13.39) isolated from neurons or endothelium are calmodulin dependent. Calmodulin binds reversibly to neuronal NO synthase in response to elevated Ca2+, triggering its NO production by an unknown mechanism. Here we show that calmodulin binding allows NADPH-derived electrons to pass onto the heme group of neuronal NO synthase. Calmodulin-triggered electron transfer to heme was independent of substrate binding, caused rapid enzymatic oxidation of NADPH in the presence of O2, and was required for NO synthesis. An NO synthase isolated from cytokine-induced macrophages that contains tightly bound calmodulin catalyzed spontaneous electron transfer to its heme, consistent with bound calmodulin also enabling electron transfer within this isoform. Together, these results provide a basis for how calmodulin may regulate NO synthesis. The ability of calmodulin to trigger electron transfer within an enzyme is unexpected and represents an additional function for calcium-binding proteins in biology.
National Acad Sciences