title: The active site of oxidative phosphorylation and the origin of hyperhomocysteinemia in aging and dementia.
abstract: The active site of oxidative phosphorylation and adenosine triphosphate (ATP) synthesis in mitochondria is proposed to consist of two molecules of thioretinamide bound to cobalamin, forming thioretinaco, complexed with ozone, oxygen, nicotinamide adenine dinucleotide. and inorganic phosphate, TR2CoO3O2NAD(+)H2PO4(-). Reduction of the pyridinium nitrogen of the nicotinamide group by an electron from electron transport complexes initiates polymerization of phosphate with adenosine diphosphate, yielding nicotinamide riboside and ATP bound to thioretinaco ozonide oxygen. A second electron reduces oxygen to hydroperoxyl radical, releasing ATP from the active site. A proton gradient is created within F1F0 ATPase complexes of mitochondria by reaction of protons with reduced nicotinamide riboside and with hydroperoxyl radical, yielding reduced nicotinamide riboside and hydroperoxide. The hyperhomocysteinemia of aging and dementia is attributed to decreased synthesis of adenosyl methionine by thioretinaco ozonide and ATP, causing decreased allosteric activation of cystathionine synthase and decreased allosteric inhibition of methylenetetrahydrofolate reductase and resulting in dysregulation of methionine metabolism.
authors.affiliation: Pathology and Laboratory Medicine Service, VA Boston Healthcare System, Harvard Medical School, Boston, Massachusetts, USA kilmer.mccully@va.gov.
authors.forename: Kilmer S
authors.initials: KS
authors.lastname: McCully
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000375:Aging / Q000473:pathology*; D031204:Caloric Restriction; D020134:Catalytic Domain; D003704:Dementia / Q000473:pathology*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D010085:Oxidative Phosphorylation; D037761:Sirtuins / Q000378:metabolism
chemical_list: D009243:NAD; D000255:Adenosine Triphosphate; D037761:Sirtuins
keywords: aging; cobalamin; dementia; homocysteine; nicotinamide adenine dinucleotide; nicotinamide riboside; oxidative phosphorylation; sirtuins; thioretinaco ozonide; thioretinamide