An elevated level of total homocysteine (tHcy) in blood, denoted hyperhomocysteinemia, is emerging as a prevalent and strong risk factor for atherosclerotic vascular disease in the coronary, cerebral, and peripheral vessels, and for arterial and venous thromboembolism. The basis for these conclusions is data from about 80 clinical and epidemiological studies including more than 10,000 patients. Elevated tHcy confers a graded risk with no threshold, is independent of but may enhance the effect of the conventional risk factors, and seems to be a particularly strong predictor of cardiovascular mortality. Hyperhomocysteinemia is attributed to commonly occurring genetic and acquired factors including deficiencies of folate and vitamin B12. Supplementation with B-vitamins, in particular with folic acid, is an efficient, safe, and inexpensive means to reduce an elevated tHcy level. Studies are now in progress to establish whether such therapy will reduce cardiovascular risk.

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Homocysteine and Cardiovascular Disease

INTRODUCTION The cell cycle is the process of vegetative (asexual) cellular reproduction; in a normal cell cycle, one cell gives rise to two cells that are genetically identical to the original cell. Questions about the cell cycle can be conveniently divided into two categories. First, one can ask how a cell carries out a cell cycle, once it has undertaken to do so. Into this category fall questions about the morphological and biochemical aspects of cell-cycle events and about the mechanisms that ensure their temporal and functional coordination. Second, one can ask what determines when a cell will undertake a cell cycle, or how the overall control of cell proliferation is achieved. Into this category fall questions about the coordination of successive cell cycles, the coordination of growth with division, the coordination of cell proliferation with the availability of essential nutrients, and the selection of developmental alternatives. In the text that follows, we consider these two categories of questions in turn. Our bibliography is intended more as a guide to the literature than as a historically accurate record of the development of the field; we apologize to the earlier workers whose contributions thus get less explicit credit than they deserve. HOW DOES A CELL CARRY OUT A CELL CYCLE? As has often been noted, successful completion of a cell cycle requires a cell to integrate the processes that duplicate the cellular material with the processes that partition the duplicated material into two viable daughter cells. Another useful formulation of the...

The Saccharomyces cerevisiae Cell Cycle

Elevated levels of homocysteine are associated with an increased risk of atherosclerosis and thrombosis. The reactivity of the sulfhydryl group of homocysteine has been implicated in molecular mechanisms underlying this increased risk. There is also increasingly compelling evidence that thiols react in the presence of nitric oxide (NO) and endothelium-derived relaxing factor (EDRF) to form S-nitrosothiols, compounds with potent vasodilatory and antiplatelet effects. We, therefore, hypothesized that S-nitrosation of homocysteine would confer these beneficial bioactivities to the thiol, and at the same time attenuate its pathogenicity. We found that prolonged (> 3 h) exposure of endothelial cells to homocysteine results in impaired EDRF responses. By contrast, brief (15 min) exposure of endothelial cells, stimulated to secrete EDRF, to homocysteine results in the formation of S-NO-homocysteine, a potent antiplatelet agent and vasodilator. In contrast to homocysteine, S-NO-homocysteine does not support H2O2 generation and does not undergo conversion to homocysteine thiolactone, reaction products believed to contribute to endothelial toxicity. These results suggest that the normal endothelium modulates the potential, adverse effects of homocysteine by releasing EDRF and forming the adduct S-NO-homocysteine. The adverse vascular properties of homocysteine may result from an inability to sustain S-NO formation owing to a progressive imbalance between the production of NO by progressively dysfunctional endothelial cells and the levels of homocysteine.

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Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..... . . . . . . . . . . . 279 Total Homocyst(e)ine and Classification of Hyperhomocyst(e)inemia . . . . . . . . . . . . . . . . . . 280 Homocysteine Metabolism and Etiology of Hyperhomocyst(e)inemia.. . . .. . . . . . . . . . . . . . 281 Vascular Disease in Severe Hyperhomocyst(e)inemia . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . ...... 283 Experimental Hyperhomocyst(e)inemia and Vascular Damage . . . . . . . . . . . . . . . . . . . . .. . . . . 284 Moderate Hyperhomocyst( e)inemia and Occlusive Arterial Disease . . . . . . . . . . . . . . . .. . . . 285 Pathogenic Mechanisms of Vascular Damage and Thromboembolism in Hyperhomocyst( e )inemia: the in vitro Studies . ..... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . 292 Concluding Remarks . . . . . . . . . .... . . . . ....... . .... . . . . . ........ . . . . ..... . . . . . . . .. . . . . . . . . . . . .. . . . . 294

Hyperhomocyst(e)inemia as a Risk Factor for Occlusive Vascular Disease

Saccharomyces cerevisiae cell cycle.

Summary: Normal hemostasis depends in part on the balance achieved between proaggregatory and prothrombotic platelet thromboxane A2, measured as its stable end-product thromboxane B2 (TXB2), and vascular prostacyclin (PGI2), which inhibits platelet aggregation and is antithrombotic. Cystathionine-β-synthase deficiency is characterized by a high frequency of thromboembolic disease. We therefore studied, in vitro, the effects of homocysteine and related compounds on platelet TXB2 and vascular PGI2 formation. In paired samples of platelet rich plasma, which had been preincubated with L-homocystine (1 mM), mean production of the two platelet cyclooxygenase products, TXB2 and 12-hydroxy-5,8,10-heptadecatrienoic acid increased significantly from control levels [13.6% ± 1.9 to 19.8% ± 2.1 (P < 0.02) TXB2 and 29.8% ± 4.2 to 39.4% ± 4.1 (P < 0.01) HHT]. In the presence of D.L-homocysteine (1 mM), mean platelet TXB2 and 12-hydroxy-5,8,10-heptadecatrienoic acid production was also significantly increased [12.7% ± 1.5 to 16.9% ± 1.5 (P < 0.01) TXB2 and 27% ± 4 to 31% ± 4.1 (P < 0.02) HHT]. Cystine, cysteine, or methionine (1 mM) did not have similar effects in this test system. Homocysteine and homocystine were without effect on the synthesis of vascular PGI2 by umbilical artery segments [control, 0.22 ± 0.03 to 0.21 ± 0.03 ng/mg with D.L-homocysteine and 0.20 ± 0.04 control to 0.19 ± 0.04 ng/mg with D.L-homocystine]. A homocyst(e)ine-induced increase in platelet thromboxane production in the absence of an increase in vascular prostacyclin, if present in vivo, may contribute to the vascular thromboses characteristic of human homocystinemias (homocystinurias).

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Effect of Homocysteine and Homocystine on Platelet and Vascular Arachidonic Acid Metabolism

The activating system of chitin synthetase from Saccharomyces cerevisiae. Purification and properties of an inhibitor of the activating factor.

Chitin synthetase activating factor from yeast, a protease.

The activating system of chitin synthetase from Saccharomyces cerevisiae. Purification and properties of the activating factor.

Publisher Summary This chapter discusses a molecular model for morphogenesis The simplest explanation of the asymmetry that results from cell separation is that the mother cell retains both the primary and secondary septa that go to form the bud scar; the daughter cell retains only a secondary septum, the birth scar If indeed chitin constitutes the primary septum, it should be synthesized during a specific period of the cell cycle, that is, prior to cell division To determine whether this was the case, a synchronous culture of Saccharomyces carlsbergensis was allowed to grow in a medium containing tritiated glucose, and the incorporation into chitin was monitored Both the polysaccharide label and the number of cells increased in stepwise fashion whereas the total radioactivity in the cells increased exponentially Polyoxins are a group of peptidyl-pyrimidine nucleoside antibiotics from Streptomyces cacaoi that are active against a variety of fungi It was considered that their site of action was related to the biosynthesis of cell wall chitin

Rodney E. Ulane

Papers

Effect of Homocysteine and Homocystine on Platelet and Vascular Arachidonic Acid Metabolism

The activating system of chitin synthetase from Saccharomyces cerevisiae. Purification and properties of an inhibitor of the activating factor.

Chitin synthetase activating factor from yeast, a protease.

The activating system of chitin synthetase from Saccharomyces cerevisiae. Purification and properties of the activating factor.

A molecular model for morphogenesis: the primary septum of yeast.