Nitric Oxide Synthase: One Enzyme, Many Functions

I like to think of Nitric Oxide Synthase as having multiple personalities. It can be mean--it can catalyze the production of nitric oxide in large quantities, which is used by the immune system to kill pathogens. It can also be really nice--it can catalyze the production of small quantities of nitric oxide which, if administered during a heart attack, causes muscle cells around blood vessels to relax and decrease glycolytic activity. 

But not only that...it can also talk!  It acts as a messenger in endothelial cells and helps regulate blood pressure by producing NO gas that is membrane permeable and vaso-active.

It even looks like an enzyme with multiple personalities...

angry face

nice face!

legs!

Nitric Oxide Synthase catalyzes the reaction that produces nitric oxide from L-arginine. NOS is found in three isoforms: brain NOS (bNOS) or neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible calcium-independent NOS (iNOS). 

NO has many important roles in the body the demand its synthesis via NOS. It activates cGMP, which mediates relaxation and prevents platelet aggregation. NO can also decrease glycolytic activity that results from heart attack by binding to glyceraldehde-3-phosphate dehydrogenase and inhibiding cellular respiration. NO also is useful in inactivating oxygen free radicals and hindering cell toxicity. 

On the other hand, under different conditions NO can react with free radical oxygen to make toxins to fight pathogens. 

The production of NO catalyzed by NOS is an extremely important mechanism due to its many physiological, biological, and pathophysiological effects in the body.

Its multiple personalities, multiple functions, and a structure that reflects those, makes it pretty much the coolest. protein. ever. :)

Works Cited:

Abu-Soud et al. “Nitric Oxide Synthases Reveal a Role for Calmodulin in Controlling Electron Transfer”. Proceedings of the National Academy of Sciences of the United States of America
90.22 (Nov. 15, 1993), pp. 10769-10772 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC303065/

Goodsell, David. Protein Data Bank Molecule of the Month: Nitric Oxide Synthase. January 2011. http://www.pdb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb133_1.html&sms_ss=twitter&at_xt=4d3eb0d8118b9af3,0

Mungrue, Imran et al. “The Role of NOS in Heart Failure: Lessons from Murine Genetic Models.” Heart Failure Reviews.7.4 (2002): 407-10. http://www.ncbi.nlm.nih.gov/pubmed/12379825

Rossellin, Marinella et al. “Role of Nitric Oxide in the Biology, Physiology, and Pathophysiology of Reproduction”. European Society for Human Reproduction and Embryology. 4.1 (1998). 3-24.http://humupd.oxfordjournals.org/content/4/1/3.abstract

Assignment 2: Nitric Oxide Synthase in the literature

Nitric Oxide Synthase (NOS) is an enzyme found in a variety of areas in the body in various forms.  The NO Synthases all produce nitric oxide in the body. In mammals, three known variations of the enzyme exist. The C-terminus of NOS shuttles electrons from NADPH to FAD and on to a heme within the N-terminal oxygenase domain. NOS catalyzes the conversion of L-arginine to NO using both domains. There are at least two steps to the reaction; the binding of oxygen to the heme and oxidation of arginine followed by a second oxygen molecule combined with the intermediate. The result is production of nitric oxide and citrulline. NOS found in neurons is important in mediating synaptic signaling. Endothelial NOS is important in regulating blood pressure by producing NO gas that is membrane permeable and vaso-active. Both of these forms are regulated by calcium-calmodulin. Cytokin-inducible NOS can produce high levels of Nitric Oxide that are toxic to the cell, which is an important mechanism of host immune response.

[Mungrue, Imran et al. “The Role of NOS in Heart Failure: Lessons from Murine Genetic Models.” Heart Failure Reviews.7.4 (2002): 407-10.]

The NO Synthases can be found in the immune, vascular, and nervous systems. In the neuronal and endothelial enzyme forms, increased levels of Ca²⁺ cause calmodulin (CAM) to bind to NOS. This activates NOS to produce nitric oxide (NO). The binding of calmodulin allows allows electrons form NADPH to be transferred to the heme group of NOS. This is a vital step in NO synthesis. In this way, calmodulin is capable of regulating NO synthesis. Thus, the NOS enzyme is another protein that is regulated by a Calmodulin-Calcium system. Macrophage NOS contains tightly bound Calmodulin, suggesting that the CAM in this instance is important in enabling NOS to remain in its active state, allowing it to be used in immune response. The NOS isoforms control electron transfer to their heme groups in different ways. Neuronal NOS transfers a greater number of electrons to its heme simply by binding of CAM.  Thus, NO is produced in response to Calcium. Macrophage NOS is tightly bound to CAM but only produces an optimal amount of NO when L-arginine binds. These differences are most likely due to the varying roles of the NOS in cell signaling in the brain versus immunomodulatory pathway control in macrophages.

[Abu-Soud et al. “Nitric Oxide Synthases Reveal a Role for Calmodulin in Controlling Electron Transfer”. Proceedings of the National Academy of Sciences of the United States of America
90.22 (Nov. 15, 1993), pp. 10769-10772]

Nitric Oxide Synthase catalyzes the reaction that produces nitric oxide from L-arginine. NOS is found in three isoforms: brain NOS (bNOS) or neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible calcium-independent NOS (iNOS). NO has many important roles in the body the demand its synthesis via NOS. It activates cGMP, which mediates relaxation and prevents platelet aggregation. NO can also decrease glycolytic activity that results from heart attack by binding to glyceraldehde-3-phosphate dehydrogenase and inhibiding cellular respiration. NO also is useful in inactivating oxygen free radicals and hindering cell toxicity. On the other hand, under different conditions NO can react with free radical oxygen to make toxins to fight pathogens. The production of NO catalyzed by NOS is an extremely important mechanism due to its many physiological, biological, and pathophysiological effects in the body.

[Rossellin, Marinella et al. “Role of Nitric Oxide in the Biology, Physiology, and Pathophysiology of Reproduction”. European Society for Human Reproduction and Embryology. 4.1 (1998). 3-24.]

[[Goodsell, David. Protein Data Bank Molecule of the Month: Nitric Oxide Synthase. January 2011. <http://www.pdb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb133_1.html>]]

Nitric Oxide Synthase: Representations

Nitric Oxide Synthase: colored by chain.

NO Synthase colored according to secondary structure.

Globular representation...butterfly?

Nitric Oxide colored by side chain.

Jellyfish.