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Homocysteine Metabolism, Atherosclerosis, and Diseases of Aging

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ABSTRACT

The importance of homocysteine in vascular function and arteriosclerosis was discovered by demonstration of arteriosclerotic plaques in children with homocystinuria caused by inherited enzymatic deficiencies of cystathionine synthase, methionine synthase, or methylene‐tetrahydrofolate reductase. According to the homocysteine theory of arteriosclerosis, an elevated blood homocysteine level is an important risk factor for atherosclerosis in subjects without these rare enzymatic abnormalities. The homocysteine theory is supported by demonstration of arterial plaques in experimental animals with hyperhomocysteinemia, by discovery of a pathway for conversion of homocysteine thiolactone to sulfate in cell cultures from children with homocystinuria, and by demonstration of growth promotion by homocysteic acid in normal and hypophysectomized animals. Studies with cultured malignant cells revealed abnormal homocysteine thiolactone metabolism, resulting in homocysteinylation of proteins, nucleic acids, and glycosaminoglycans, explaining the abnormal oxidative metabolism, abnormalities of cellular membranes, and altered genetic expression observed in malignancy. Abnormal homocysteine metabolism in malignant cells is attributed to deficiency of thioretinamide, the amide synthesized from retinoic acid and homocysteine thiolactone. Two molecules of thioretinamide combine with cobalamin to form thioretinaco. Based on the molecular structure of thioretinaco, a theory of oxidative phosphorylation was proposed, involving oxidation to a disulfonium derivative by ozone, and binding of oxygen, nicotinamide adenine dinucleotide and phosphate as the active site of adenosine triphosphate synthesis in mitochondria. Obstruction of vasa vasorum by aggregates of microorganisms with homocysteinylated low‐density lipoproteins is proposed to cause ischemia of arterial wall and a microabscess of the intima, the vulnerable atherosclerotic plaque. © 2016 American Physiological Society. Compr Physiol 6:471‐505, 2016.

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Figure 1. Figure 1. Chemical synthesis, hydrolysis, oxidation, and polymerization reactions of homocysteine thiolactone are indicated. Reprinted from Ref. () with permission.
Figure 2. Figure 2. Biochemical pathways of synthesis of homocysteine thiolactone, adenosyl methionine and homocysteine are indicated. Inherited deficiencies of (i) cystathionine synthase, (ii) methyltetrahydrofolate homocysteine methyl transferase, and (iii) methylenetetrahydrofolate reductase cause accumulation of homocystine and homocysteine cysteine disulfide in tissues and body fluids. Reprinted from Ref. () with permission.
Figure 3. Figure 3. The chemical structures of N‐substituted derivatives of homocysteine thiolactone are indicated. The effects of these compounds on carcinogenesis and on growth of transplanted neoplasms are indicated in parenthesis. Reprinted from Ref. () with permission.
Figure 4. Figure 4. Thioretinaco is bound to lipid bilayer of mitochondrial and microsomal membranes by interaction of thioretinamide groups with the hydrophobic core of the membrane. Reprinted from Ref. () with permission.
Figure 5. Figure 5. The disulfonium oxygen ascorbate active site of membrane bound thioretinaco ozonide promotes binding of ATP from F1 complex, proton pumping from F1 complex, and electron flow from electron transport complexes, followed by release of ATP and formation of monodehydroascorbate. Reprinted from Ref. () with permission.
Figure 6. Figure 6. Stereochemistry of disulfonium active site of thioretinaco ozonide accommodates binding of the alpha and gamma phosphate anions of ATP. Reprinted from Ref. () with permission.
Figure 7. Figure 7. The oxygen complex with thioretinaco ozonide is reduced by electrons from electron transport and neutralized by protons from proton pump, providing six energy levels of bound oxygen that bind ATP during oxidative phosphorylation. Reprinted from Ref. () with permission.
Figure 8. Figure 8. Correlation between plasma homocysteine and transthyretin concentrations in protein malnutrition. Values are plotted for control subjects (C), both male (M) and female (F), and for subjects with stages I, II, and III of protein energy malnutrition according to WHO criteria. Values are expressed as mean ± standard deviation (horizontal and vertical bars). Reprinted from Ref. () with permission.
Figure 9. Figure 9. Scheme for synthesis of thioretinamide, oxidation to sulfite and sulfate, and activation of sulfate to PAPS explains sulfation of glycosaminoglycans (GAG) to form sulfate esters. Reprinted from Ref. () with permission.
Figure 10. Figure 10. Development of the vulnerable atherosclerotic plaque. The small globules inside the vasa vasorum and in the vulnerable plaque represent lipoproteins; the black dots represent microorganisms, endotoxins, anti‐OxLDL autoantibodies, and antihomocysteinylated LDL autoantibodies; the large globules at the basal part of the vulnerable plaque and inside the macrophages represent lipid droplets. The right vasa vasorum vasa vasorum represents the status of a normal healthy arteriole, where only a few microbes and lipoproteins are able to traverse the lumen without adherence or obstruction. The left vasa vasorum represents the status of an arteriole with severe microbial invasion, where microbial products and autoantibodies adhere to the lipoproteins, which aggregate and obstruct the lumen, leading to local ischemia, microbial growth and inflammation. A monocyte enters the plaque from the arterial lumen by diapedesis between endothelial cells, and another monocyte enters the plaque from the vasa vasorum, leading to foam cell macrophages within the plaque. With a healthy immune system the inflammatory exudate heals and becomes converted to a fibrous plaque. With an insufficient immune system, microorganisms escape into the wall of the artery and intima, creating a microabscess, the vulnerable atherosclerotic plaque. Reprinted from Ref. () with permission.
Figure 11. Figure 11. Scheme for adenosyl methionine synthesis from methionine requires thioretinaco ozonide, oxygen, and ATP. Reprinted from Ref. () with permission.
Figure 12. Figure 12. Scheme for homocysteine thiolactone synthesis from methionine requires thioco. Reprinted from Ref. () with permission.


Figure 1. Chemical synthesis, hydrolysis, oxidation, and polymerization reactions of homocysteine thiolactone are indicated. Reprinted from Ref. () with permission.


Figure 2. Biochemical pathways of synthesis of homocysteine thiolactone, adenosyl methionine and homocysteine are indicated. Inherited deficiencies of (i) cystathionine synthase, (ii) methyltetrahydrofolate homocysteine methyl transferase, and (iii) methylenetetrahydrofolate reductase cause accumulation of homocystine and homocysteine cysteine disulfide in tissues and body fluids. Reprinted from Ref. () with permission.


Figure 3. The chemical structures of N‐substituted derivatives of homocysteine thiolactone are indicated. The effects of these compounds on carcinogenesis and on growth of transplanted neoplasms are indicated in parenthesis. Reprinted from Ref. () with permission.


Figure 4. Thioretinaco is bound to lipid bilayer of mitochondrial and microsomal membranes by interaction of thioretinamide groups with the hydrophobic core of the membrane. Reprinted from Ref. () with permission.


Figure 5. The disulfonium oxygen ascorbate active site of membrane bound thioretinaco ozonide promotes binding of ATP from F1 complex, proton pumping from F1 complex, and electron flow from electron transport complexes, followed by release of ATP and formation of monodehydroascorbate. Reprinted from Ref. () with permission.


Figure 6. Stereochemistry of disulfonium active site of thioretinaco ozonide accommodates binding of the alpha and gamma phosphate anions of ATP. Reprinted from Ref. () with permission.


Figure 7. The oxygen complex with thioretinaco ozonide is reduced by electrons from electron transport and neutralized by protons from proton pump, providing six energy levels of bound oxygen that bind ATP during oxidative phosphorylation. Reprinted from Ref. () with permission.


Figure 8. Correlation between plasma homocysteine and transthyretin concentrations in protein malnutrition. Values are plotted for control subjects (C), both male (M) and female (F), and for subjects with stages I, II, and III of protein energy malnutrition according to WHO criteria. Values are expressed as mean ± standard deviation (horizontal and vertical bars). Reprinted from Ref. () with permission.


Figure 9. Scheme for synthesis of thioretinamide, oxidation to sulfite and sulfate, and activation of sulfate to PAPS explains sulfation of glycosaminoglycans (GAG) to form sulfate esters. Reprinted from Ref. () with permission.


Figure 10. Development of the vulnerable atherosclerotic plaque. The small globules inside the vasa vasorum and in the vulnerable plaque represent lipoproteins; the black dots represent microorganisms, endotoxins, anti‐OxLDL autoantibodies, and antihomocysteinylated LDL autoantibodies; the large globules at the basal part of the vulnerable plaque and inside the macrophages represent lipid droplets. The right vasa vasorum vasa vasorum represents the status of a normal healthy arteriole, where only a few microbes and lipoproteins are able to traverse the lumen without adherence or obstruction. The left vasa vasorum represents the status of an arteriole with severe microbial invasion, where microbial products and autoantibodies adhere to the lipoproteins, which aggregate and obstruct the lumen, leading to local ischemia, microbial growth and inflammation. A monocyte enters the plaque from the arterial lumen by diapedesis between endothelial cells, and another monocyte enters the plaque from the vasa vasorum, leading to foam cell macrophages within the plaque. With a healthy immune system the inflammatory exudate heals and becomes converted to a fibrous plaque. With an insufficient immune system, microorganisms escape into the wall of the artery and intima, creating a microabscess, the vulnerable atherosclerotic plaque. Reprinted from Ref. () with permission.


Figure 11. Scheme for adenosyl methionine synthesis from methionine requires thioretinaco ozonide, oxygen, and ATP. Reprinted from Ref. () with permission.


Figure 12. Scheme for homocysteine thiolactone synthesis from methionine requires thioco. Reprinted from Ref. () with permission.
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Further reading list
Carmel R, Jacobsen DW.  Homocysteine in Health and Disease.  Cambridge UK:  Cambridge University Press, 2001.
DuVigneaud V.  A Trail of Research in Sulfur Chemistry and Metabolism.  Ithaca NY:  Cornell University Press, 1952.
Graham I, Refsum H, Rosenberg IH, Ueland PM, Editors.  Homocysteine Metabolism: From Basic Science to Clinical Medicine.  Boston:  Kluwer Academic Publishers, 1997.
McCully KS.  The Homocysteine Revolution.  Medicine for the New Millennium.  Los Angeles:  Keats Publishing, Division of NTC/Contemporary Publishing Group, 1999.
McCully KS, McCully M.  The Heart Revolution.   The Extraordinary Discovery that Finally Laid the Cholesterol Myth to Rest.  New York:  HarperCollins Perennial, 2000.
McCully KS.  Pioneer of the Homocysteine Theory.  New York: Nova Science Publishers, 2013.
McCully KS, Editor.  Homocysteine: Biosynthesis and Health Implications. New York:  Nova Science Publishers, 2014.
Robinson K, Editor.  Homocysteine and Vascular Disease.  Dordrecht, Netherlands:  Kluwer Academic Publishers, 2000.
Stanger O.  Homocystein.  Grundlagen, Klinik, Therapie, Prävention.  Wein:  Wilhelm Maudrich, 2004 [In German].


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Kilmer S. McCully. Homocysteine Metabolism, Atherosclerosis, and Diseases of Aging. Compr Physiol 2015, 6: 471-505. doi: 10.1002/cphy.c150021