Irreversible Inhibition of Lysyl Oxidase by Homocysteine Thiolactone and Its Selenium and Oxygen Analogues

Liu, Guanmei; Nellaiappan, Kaliappanadar; Kagan, Herbert M.

doi:10.1074/jbc.272.51.32370

Cited by 120 publications

(64 citation statements)

References 41 publications

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“…Hcy-thiolactone, but not Hcy, was found to induce gross changes in human endothelial cell morphology and to induce cell death with apoptotic features (30). These effects are likely to be caused by Hcy-thiolactone-mediated formation of Hcy-N-protein, which results in protein damage (17,27,28). However, the role of Hcy-N-protein in Hcy-induced toxicity has not been examined.…”

Section: Homocysteine Is a Protein Amino Acid In Humans 30427mentioning

confidence: 99%

Homocysteine Is a Protein Amino Acid in Humans

Jakubowski

2002

Journal of Biological Chemistry

175

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Homocysteine is thought to be a non-protein amino acid. However, in vitro studies suggest that homocysteine is likely to be incorporated by indirect mechanisms into proteins in living organisms. Here I show that homocysteine is a protein amino acid in humans. Homocysteine bound by amide or peptide linkages (Hcy-N-protein) is present in human hemoglobin, serum albumin, and ␥-globulins. 1 molecule of homocysteine per 1000 or 1670 molecules of methionine was present in hemoglobin or albumin, respectively. Other proteins, such as low density lipoprotein, high density lipoprotein, transferrin, antitrypsin, and fibrinogen, contained lower amounts of Hcy-N-protein. In human plasma, levels of Hcy-N-protein represented from 0.3 to 23% of total homocysteine. Thus, Hcy-N-protein is a significant component of homocysteine metabolism in humans, possibly contributing to adverse effects of homocysteine on human cells.It has been known for 4 decades that elevated levels of homocysteine (Hcy) 1 are harmful to humans (1, 2), but over the past decade it has been established that even a mild increase in Hcy level is a risk factor for cardiovascular disease and stroke in humans (3) and predicts mortality independently of traditional risk factors in patients with coronary artery disease (4). Plasma Hcy is also a risk factor for dementia and Alzheimer's disease (5). However, mechanisms by which Hcy can be harmful are largely unknown.In humans Hcy is formed from methionine as a by-product of biological methylation reactions (1, 2). If not removed by transsulfuration and transmethylation reactions, Hcy becomes toxic to human cells (1, 2), possibly due to its indirect incorporation into protein by methionyl-tRNA synthetase (MetRS)-mediated mechanisms involving S-nitroso-Hcy or Hcy-thiolactone (6 -11) (Fig. 1). A translational pathway includes: (a) reaction of Hcy with nitric oxide, forming S-nitroso-Hcy (12), (b) attachment of S-nitroso-Hcy to tRNA Met catalyzed by MetRS, forming S-nitroso-Hcy-tRNA Met (13), and (c) transfer of S-nitroso-Hcy from S-nitroso-Hcy-tRNAMet into growing polypeptide chains on ribosomes (13). Transnitrosylation of S-nitroso-Hcy-protein results in the formation of protein chains containing Hcy at positions normally occupied by methionine (13). A post-translational pathway involves: (a) metabolic conversion of Hcy to Hcy-thiolactone by MetRS (14 -16) and (b) acylation of protein lysine residues by . Because N-homocysteinylation leads to protein damage, we hypothesized that this aspect of Hcy metabolism provides a plausible chemical mechanism accounting at least in part for the toxicity of Hcy in humans (6 -11, 15-17).It is not known whether protein N-homocysteinylation occurs in humans. To determine this, human blood proteins were analyzed for the presence of Hcy bound by amide or peptide linkages (Hcy-N-protein) using protein chemistry and HPLC methods. As described in this communication, Hcy is a protein amino acid in humans. MATERIALS AND METHODS Preparation of L-[ 35 S]Hcy-thiolactone-[35 S]Hcy-thiolactone (...

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Section: Homocysteine Is a Protein Amino Acid In Humans 30427mentioning

confidence: 99%

Homocysteine Is a Protein Amino Acid in Humans

Jakubowski

2002

Journal of Biological Chemistry

175

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“…Lane M shows the molecular weight markers (Bio-Rad). The 24-kDa protein that co-purifies with lysyl oxidase seen in lane P has previously been identified as the tyrosine-rich acidic matrix protein (TRAMP) (75,76 I, suramin increased lysyl oxidase activity in RS485 cell media by a factor of 2.2. This relatively small increase in enzyme activity in suramin-treated RS485 cells compared with mRNA increases is consistent with our finding of predominant production of unprocessed 50-kDa pro-lysyl oxidase summarized in Fig.…”

Section: Effect Of Suramin On Active Lysylmentioning

confidence: 99%

Autocrine Growth Factor Regulation of Lysyl Oxidase Expression in Transformed Fibroblasts

Palamakumbura

Sommer

Trackman

2003

Journal of Biological Chemistry

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Lysyl oxidase catalyzes oxidative deamination of peptidyl-lysine and hydroxylysine residues in collagens and lysine residues in elastin to form peptidyl aldehydes that are required for the formation of covalent crosslinks in normal extracellular matrix biosynthesis. Lysyl oxidase in addition has tumor suppressor activity, and phenotypic reversion of transformed cell lines is accompanied by increased lysyl oxidase expression. The mechanism of low expression of lysyl oxidase in tumor cells is unknown. The present study investigates the hypothesis that autocrine growth factor pathways maintain low lysyl oxidase expression levels in c-H-ras-transformed fibroblasts (RS485 cell line). Autocrine pathways were blocked with suramin, a general inhibitor of growth factor receptor binding, and resulted in more than a 10-fold increase in lysyl oxidase expression and proenzyme production. This regulation was found to be reversible and occurred at the transcriptional level determined using lysyl oxidase promoter/reporter gene assays. Function blocking anti-fibroblast growth factor-2 (FGF-2) antibody enhanced lysyl oxidase expression in the absence of suramin. Finally, the addition of FGF-2 to suramin-treated cells completely reversed suramin stimulation of lysyl oxidase mRNA levels. Data support that an FGF-2 autocrine pathway inhibits lysyl oxidase transcription in the tumorigenic-transformed RS485 cell line. This finding may be of therapeutic significance and, in addition, provides a new experimental approach to investigate the mechanism of the tumor suppressor activity of lysyl oxidase.

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“…Although the increase in LOX activity was associated with enhanced mRNA and protein expression, a direct influence of reactive oxygen species on the active form of the enzyme has been proposed (41). Finally, homocysteine thiolactone, which occurs in mammalian systems as a metabolic by-product of methyl transfer from S-adenosylhomocysteine, is able to directly inhibit LOX activity through a direct covalent interaction with the enzyme carbonyl cofactor lysine tyrosylquinone (LTQ) (37).…”

Section: The Lox Enzymementioning

confidence: 99%

Role of lysyl oxidase in myocardial fibrosis: from basic science to clinical aspects

López

González

Hermida

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

222

198

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Because of its dynamic nature, the composition and structure of the myocardial collagen network can be reversibly modified to adapt to transient cardiac injuries. In response to persistent injury, however, irreversible, maladaptive changes of the network occur leading to fibrosis, mostly characterized by the excessive interstitial and perivascular deposition of collagen types I and III fibers. It is now becoming apparent that myocardial fibrosis directly contributes to adverse myocardial remodeling and the resulting alterations of left ventricular (LV) anatomy and function present in the major types of cardiac diseases. The enzyme lysyl oxidase (LOX) is a copper-dependent extracellular enzyme that catalyzes lysine-derived cross-links in collagen and elastin. LOXmediated cross-linking of collagen types I and III fibrils leads to the formation of stiff collagen types I and III fibers and their subsequent tissue deposition. Evidence from experimental and clinical studies shows that the excess of LOX is associated with an increased collagen cross-linking and stiffness. It is thus conceivable that LOX upregulation and/or overactivity could underlie myocardial fibrosis and altered LV mechanics and contribute to the compromise of LV function in cardiac diseases. This review will consider the molecular aspects related to the regulation and actions of LOX, namely, in the context of collagen synthesis. In addition, it will address the information related to the role of myocardial LOX in heart failure and the potential benefits of controlling its expression and function. collagen; diastolic dysfunction; hypertensive heart disease; myocardial remodeling THE ELEVATION IN myocardial stress that results from cardiac injury and/or persistent elevations in ventricular pressure or volume triggers a response of the myocardium in an attempt to return the tissue stress to its normal value. This response leads to progressive structural remodeling of the cardiomyocyte, vascular and extracellular matrix (ECM) components of the myocardium that manifest as changes in ventricular wall and chamber dimensions, as well as in diastolic and systolic function (5).Alterations in the myocardial collagen network are a hallmark of the ECM response to stress, either hemodynamic or nonhemodynamic in origin. A collagen network, composed largely of collagen types I and III fibers, is found in the interstitial space of the myocardium. Because collagen is a relatively stiff material with a high-tensile strength, small changes in its concentration have been shown to exert marked effects on the passive mechanical properties of the human heart (7). In addition to the concentration of collagen, experimental data suggest that the passive behavior of the myocardium may also be dependent on the relative proportion of the types of collagen, the diameter of the collagen fibers and their spatial alignment, and the degree of cross-linking. Accordingly, tissue containing predominantly type I collagen, large-diameter collagen fibers, and/or a high degree of cross-lin...

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Irreversible Inhibition of Lysyl Oxidase by Homocysteine Thiolactone and Its Selenium and Oxygen Analogues

Cited by 120 publications

References 41 publications

Homocysteine Is a Protein Amino Acid in Humans

Homocysteine Is a Protein Amino Acid in Humans

Autocrine Growth Factor Regulation of Lysyl Oxidase Expression in Transformed Fibroblasts

Role of lysyl oxidase in myocardial fibrosis: from basic science to clinical aspects

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