Modellversuche zur oxydativen Phosphorylierung, VII. <i>N</i>‐Acetyl‐homocysteinthiolacton als Vermittler einer oxydativen Synthese von Adenosindiphosphat und Adenosintriphosphat aus Adenosinmonophosphat und Orthophosphat

Wieland, Theodor; Bäuerlein, Edmund

doi:10.1002/cber.19671001208

Cited by 22 publications

(2 citation statements)

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“…Ozone reacts with alkyl sulfide to produce alkyl sulfide ozonide, a compound in which the sulfur atom is oxidized to sulfonium radical (253). The resistance of homocysteine thiolactone to oxidation by perchloric acid (298) or by bromine (335) suggests that a disulfonium ozonide may stabilize the active site by forming an ozone bridge between the two sulfur atoms of thioretinaco. Thioretinaco ozonide is capable of reacting with oxygen, as shown by formation of ozone-oxygen clusters of the O 3 (O 2 + ) type (56).…”

Section: Thioretinamide Thioretinaco Carcinogenesis and Atherogenesismentioning

confidence: 99%

Homocysteine Metabolism, Atherosclerosis, and Diseases of Aging

McCully

2015

Comprehensive Physiology

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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.

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Section: Thioretinamide Thioretinaco Carcinogenesis and Atherogenesismentioning

confidence: 99%

Homocysteine Metabolism, Atherosclerosis, and Diseases of Aging

McCully

2015

Comprehensive Physiology

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“…As described elsewhere [2,3,10] it was separated by quantitative thin-layer chromatography. The eluates were analyzed for ATP by the phosphoglycerate-kinase method of Bucher [ill, followed by a further assay by the myokinase method of Gruber c121-…”

Section: Analysis Of the Reaction Mixturementioning

confidence: 99%

Iodine, Hemin and Heminester as Oxidants in a Synthesis of ATP from ADP and P_i Mediated by Thiols and Disulfides

Bäuerlein

Klingenfuss

Wieland

1971

European Journal of Biochemistry

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The conversion of oxidation energy into the energy-rich phosphoryl linkage of ATP has been demonstrated in a system consisting of the tertiary-butylammonium salts of ADP and Pi in pyridine and utilising several mercapto carboxylic acids or their disulfides as mediators and iodine or hemin or hemindimethyl ester as oxidants.Iodine with several thiols in 1 : 1 molar proportions produces relatively poor yields of ATP (1.5-5.401,) which can be considerably increased ( 10-15°/0) when the corresponding disulfides are used, whereas a thioether (N-acetylmethionine) had no effect. This led to the conclusion that disulfides are better substrates and accordingly much higher amounts of ATP were formed from all thiols on using a two-fold amount of oxidant (up to 25.6O1,). Taking this into account a mechanism has been formulated in which the formation of a phosphorylating species, RS-OPO,H,, is assumed to be formed from disulfides.Hemin and (less efficiently) its dimethyl ester used as oxidants also give rise to the formation of ATP in our system, but only under aerobic conditions. Here optimal yields (up to 16.701,) were obtained with thioglycolate or its disulfide as mediators, a thioether (N-acetylmethionine) being almost ineffective, and no difference in efficiency between thiol acid and disuKde was observed at a hemin : sulfur ratio of 1 : 1. The yields depend in some way on the hemin : S ratio, lower values giving higher amounts of ATP on oxidation of the mercapto compound, but not of its disuEde. Therefore a reaction mechanism Werent from that of iodine must be presumed. The formation of the same phosphorylating species as above has been assumed to occur preferently with a thiol and to a lesser extent with a disulfide. The role of oxygen is still rather obscure, for it can not be determined whether it is the terminal electron acceptor or electron carrier. A catalytic participation of hemin could not be demonstrated, perhaps on account of the slow autoxidation rate of the ferrous heme iron.The basic mechanism of mitochondria1 oxidative phosphorylation, the process by which the energy of electron transport is converted into the high energy pyrophosphate bond of ATP, is still rather obscure. I n order to produce a chemical hypothesis which includes the formation of high-energy intermediates during electron transfer, model reactions are being studied in several laboratories (for a recent review see [l] surprisingly the oxidation by bromine (5equiv.) of a simple thiol, like thioglycolic acid under anhydrous conditions (pyridine) led to the formation of a yield as high as 35O/, ATP from ADP and Pi [2]. In this system, a t every step of oxidation leading eventually t o the highest oxidized state of sulfur (hexavalent), a coupled phosphorylation can occur. In order to simplify the system we have studied the effect of the milder oxidizing agent, iodine. Simultaneously the number of mediator compounds investigated as models for protein bound sulfur was extended to 2-mercaptopropionic acid, N-acetylcysteine, their corresponding d...

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Bildung von Adenosintriphosphat (ATP) aus Adenosindiphosphat (ADP) und Phosphat während der Oxidation von Monoacetyl‐durohydrochinon

Wieland

Aquila

1968

Angewandte Chemie

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Modellversuche zur oxydativen Phosphorylierung, VII. N‐Acetyl‐homocysteinthiolacton als Vermittler einer oxydativen Synthese von Adenosindiphosphat und Adenosintriphosphat aus Adenosinmonophosphat und Orthophosphat

Cited by 22 publications

References 14 publications

Homocysteine Metabolism, Atherosclerosis, and Diseases of Aging

Homocysteine Metabolism, Atherosclerosis, and Diseases of Aging

Iodine, Hemin and Heminester as Oxidants in a Synthesis of ATP from ADP and P_i Mediated by Thiols and Disulfides

Bildung von Adenosintriphosphat (ATP) aus Adenosindiphosphat (ADP) und Phosphat während der Oxidation von Monoacetyl‐durohydrochinon

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Modellversuche zur oxydativen Phosphorylierung, VII. N‐Acetyl‐homocysteinthiolacton als Vermittler einer oxydativen Synthese von Adenosindiphosphat und Adenosintriphosphat aus Adenosinmonophosphat und Orthophosphat

Cited by 22 publications

References 14 publications

Homocysteine Metabolism, Atherosclerosis, and Diseases of Aging

Homocysteine Metabolism, Atherosclerosis, and Diseases of Aging

Iodine, Hemin and Heminester as Oxidants in a Synthesis of ATP from ADP and Pi Mediated by Thiols and Disulfides

Bildung von Adenosintriphosphat (ATP) aus Adenosindiphosphat (ADP) und Phosphat während der Oxidation von Monoacetyl‐durohydrochinon

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Iodine, Hemin and Heminester as Oxidants in a Synthesis of ATP from ADP and P_i Mediated by Thiols and Disulfides