Is Endothelial Nitric Oxide Synthase a Moonlighting Protein Whose Day Job is Cholesterol Sulfate Synthesis? Implications for Cholesterol Transport, Diabetes and Cardiovascular Disease

Abstract

Theoretical inferences, based on biophysical, biochemical, and biosemiotic considerations, are related here to the pathogenesis of cardiovascular disease, diabetes, and other degenerative conditions. We suggest that the "daytime" job of endothelial nitric oxide synthase (eNOS), when sunlight is available, is to catalyze sulfate production. There is a striking alignment between cell types that produce either cholesterol sulfate or sulfated polysaccharides and those that contain eNOS. The signaling gas, nitric oxide, a wellknown product of eNOS, produces pathological effects not shared by hydrogen sulfide, a sulfur-based signaling gas. We propose that sulfate plays an essential role in HDL-A1 cholesterol trafficking and in sulfation of heparan sulfate proteoglycans (HSPGs), both critical to lysosomal recycling (or disposal) of cellular debris. HSPGs are also crucial in glucose metabolism, protecting against diabetes, and in maintaining blood colloidal suspension and capillary flow, through systems dependent on water-structuring properties of sulfate, an anionic kosmotrope. When sunlight exposure is insufficient, lipids accumulate in the atheroma in order to supply cholesterol and sulfate to the heart, using a OPEN ACCESSEntropy 2012, 14 2493 process that depends upon inflammation. The inevitable conclusion is that dietary sulfur and adequate sunlight can help prevent heart disease, diabetes, and other disease conditions.

Biological Water Dynamics and Entropy: A Biophysical Origin of Cancer and Other Diseases

“…Data have been presented suggesting that Al uncouples erythrocytic NOS, interfering with sulfate synthesis, possibly by displacing zinc in the cavity formed between the two monomers of the molecule [2,276]. This disruption results in peroxynitrite production through the reaction of superoxide with nitric oxide.…”

Glucosamine Sodium Sulfate Can Penetrate Skin and May Affect Glucose Metabolism in Rats

“…Its activation requires the entry of calcium, angiotensin and adrenergic agonists, which implicated in hypertension, diabetes and heart disease. This suggests the sulfate supplied in GlcNs maybe play a beneficial effect in kidney [37,38].…”

Can glyphosate’s disruption of the gut microbiome and induction of sulfate deficiency explain the epidemic in gout and associated diseases in the industrialized world?

“…Red blood cells are negatively charged, in part due to sialic acid in the membrane glycoproteins [108] and in part due to cholesterol sulfate [102,107]. The movement of negatively charged particles engenders an electrokinetic vascular streaming potential (EVSP), which is proportional to the pressure and to the zeta potential, which depends on the negative charge density, and inversely proportional to the viscosity of the medium.…”

“…This can lead, through reaction with NO, to the production of peroxynitrite (ONOO -), an extremely destructive oxidizing agent. It has been proposed that eNOS is a "moonlighting" enzyme, switching between oxidizing nitrogen or sulfur depending on the external environment [102,107]. Superoxide is used to oxidize sulfur when eNOS is bound to caveolin in the membrane, whereas phosphorylated calmodulin induces eNOS to detach from the membrane and synthesize NO instead, following phosphorylation.…”