scholarly journals Targeted Disruption of the Methionine Synthase Gene in Mice

2001 ◽  
Vol 21 (4) ◽  
pp. 1058-1065 ◽  
Author(s):  
Deborah A. Swanson ◽  
Mei-Lan Liu ◽  
Priscilla J. Baker ◽  
Lisa Garrett ◽  
Michael Stitzel ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Megaloblastic Anemia ◽  
Plasma Homocysteine ◽  
Methionine Synthase ◽  
Vitamin B ◽  
Compensatory Mechanism ◽  
Elevated Plasma ◽  
Wild Type ◽  
Targeted Disruption ◽  
Methyl Group

ABSTRACT Alterations in homocysteine, methionine, folate, and/or B12 homeostasis have been associated with neural tube defects, cardiovascular disease, and cancer. Methionine synthase, one of only two mammalian enzymes known to require vitamin B12 as a cofactor, lies at the intersection of these metabolic pathways. This enzyme catalyzes the transfer of a methyl group from 5-methyl-tetrahydrofolate to homocysteine, generating tetrahydrofolate and methionine. Human patients with methionine synthase deficiency exhibit homocysteinemia, homocysteinuria, and hypomethioninemia. They suffer from megaloblastic anemia with or without some degree of neural dysfunction and mental retardation. To better study the pathophysiology of methionine synthase deficiency, we utilized gene-targeting technology to inactivate the methionine synthase gene in mice. On average, heterozygous knockout mice from an outbred background have slightly elevated plasma homocysteine and methionine compared to wild-type mice but seem to be otherwise indistinguishable. Homozygous knockout embryos survive through implantation but die soon thereafter. Nutritional supplementation during pregnancy was unable to rescue embryos that were completely deficient in methionine synthase. Whether any human patients with methionine synthase deficiency have a complete absence of enzyme activity is unclear. These results demonstrate the importance of this enzyme for early development in mice and suggest either that methionine synthase-deficient patients have residual methionine synthase activity or that humans have a compensatory mechanism that is absent in mice.

scholarly journals Generation of a Mouse Model for Arginase II Deficiency by Targeted Disruption of the Arginase II Gene

2001 ◽  
Vol 21 (3) ◽  
pp. 811-813 ◽  
Author(s):  
Ou Shi ◽  
Sidney M. Morris ◽  
Huda Zoghbi ◽  
Carl W. Porter ◽  
William E. O'Brien
Keyword(s):  
Urea Cycle ◽  
Elevated Plasma ◽  
Wild Type ◽  
Targeted Disruption ◽  
Arginase Ii ◽  
Plasma Arginine ◽  
Physiologic Role ◽  
Deficient Mice ◽  
Arginase I

ABSTRACT Mammals express two isoforms of arginase, designated types I and II. Arginase I is a component of the urea cycle, and inherited defects in arginase I have deleterious consequences in humans. In contrast, the physiologic role of arginase II has not been defined, and no deficiencies in arginase II have been identified in humans. Mice with a disruption in the arginase II gene were created to investigate the role of this enzyme. Homozygous arginase II-deficient mice were viable and apparently indistinguishable from wild-type mice, except for an elevated plasma arginine level which indicates that arginase II plays an important role in arginine homeostasis.

scholarly journals Interrelations between Glycine Betaine Catabolism and Methionine Biosynthesis in Sinorhizobium meliloti Strain 102F34

2006 ◽  
Vol 188 (20) ◽  
pp. 7195-7204 ◽  
Author(s):  
Lise Barra ◽  
Catherine Fontenelle ◽  
Gwennola Ermel ◽  
Annie Trautwetter ◽  
Graham C. Walker ◽  
...  
Keyword(s):  
Glycine Betaine ◽  
Sinorhizobium Meliloti ◽  
Wild Type Strain ◽  
Methionine Synthase ◽  
Vitamin B ◽  
Wild Type ◽  
Methionine Biosynthesis ◽  
Catabolic Pathway ◽  
Methyl Transferase ◽  
Meliloti Strain

ABSTRACT Methionine is produced by methylation of homocysteine. Sinorhizobium meliloti 102F34 possesses only one methionine synthase, which catalyzes the transfer of a methyl group from methyl tetrahydrofolate to homocysteine. This vitamin B12-dependent enzyme is encoded by the metH gene. Glycine betaine can also serve as an alternative methyl donor for homocysteine. This reaction is catalyzed by betaine-homocysteine methyl transferase (BHMT), an enzyme that has been characterized in humans and rats. An S. meliloti gene whose product is related to the human BHMT enzyme has been identified and named bmt. This enzyme is closely related to mammalian BHMTs but has no homology with previously described bacterial betaine methyl transferases. Glycine betaine inhibits the growth of an S. meliloti bmt mutant in low- and high-osmotic strength media, an effect that correlates with a decrease in the catabolism of glycine betaine. This inhibition was not observed with other betaines, like homobetaine, dimethylsulfoniopropionate, and trigonelline. The addition of methionine to the growth medium allowed a bmt mutant to recover growth despite the presence of glycine betaine. Methionine also stimulated glycine betaine catabolism in a bmt strain, suggesting the existence of another catabolic pathway. Inactivation of metH or bmt did not affect the nodulation efficiency of the mutants in the 102F34 strain background. Nevertheless, a metH strain was severely defective in competing with the wild-type strain in a coinoculation experiment.

Plasma homocysteine levels in L-dopa-treated Parkinson's disease patients with cognitive dysfunctions

2005 ◽  
Vol 43 (10) ◽  
Author(s):  
Stefano Zoccolella ◽  
Paolo Lamberti ◽  
Giovanni Iliceto ◽  
Cosimo Diroma ◽  
Elio Armenise ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Plasma Homocysteine ◽  
Vitamin B ◽  
Elevated Plasma ◽  
Cognitive Dysfunctions ◽  
The Relationship ◽  
Late Stages

AbstractElevated plasma homocysteine (Hcy) concentrations are associated with Alzheimer's disease and vascular dementia. Several recent reports have indicated that L-dopa treatment is an acquired cause of hyperhomo-cysteinemia. Despite the fact that a large proportion of Parkinson's disease (PD) patients develop cognitive dysfunctions or dementia, particularly in the late stages of the illness and after long-term L-dopa treatment, the relationship between Hcy and dementia in PD has not been fully investigated. The aim of this study was to evaluate plasma Hcy levels in a group of L-dopa-treated PD patients with cognitive impairment and to elucidate a possible role of Hcy in the development of cognitive dysfunctions in PD. We compared Hcy, vitamin B

scholarly journals Methylation demand: a key determinant of homocysteine metabolism.

2004 ◽  
Vol 51 (2) ◽  
pp. 405-413 ◽  
Author(s):  
John T Brosnan ◽  
Rene L Jacobs ◽  
Lori M Stead ◽  
Margaret E Brosnan
Keyword(s):  
Pyridoxal Phosphate ◽  
Homocysteine Level ◽  
Plasma Homocysteine ◽  
Methionine Synthase ◽  
Elevated Plasma ◽  
Plasma Homocysteine Level ◽  
Vitamin Status ◽  
The Many ◽  
B Vitamin ◽  
Quantitative Importance

Elevated plasma homocysteine is a risk factor for cardiovascular disease and Alzheimer's disease. To understand the factors that determine the plasma homocysteine level it is necessary to appreciate the processes that produce homocysteine and those that remove it. Homocysteine is produced as a result of methylation reactions. Of the many methyltransferases, two are, normally, of the greatest quantitative importance. These are guanidinoacetate methyltransferase (that produces creatine) and phosphatidylethanolamine N-methyltransferase (that produces phosphatidylcholine). In addition, methylation of DOPA in patients with Parkinson's disease leads to increased homocysteine production. Homocysteine is removed either by its irreversible conversion to cysteine (transsulfuration) or by remethylation to methionine. There are two separate remethylation reactions, catalyzed by betaine:homocysteine methyltransferase and methionine synthase, respectively. The reactions that remove homocysteine are very sensitive to B vitamin status as both the transsulfuration enzymes contain pyridoxal phosphate, while methionine synthase contains cobalamin and receives its methyl group from the folic acid one-carbon pool. There are also important genetic influences on homocysteine metabolism.

scholarly journals Defects in homocysteine metabolism: diversity among hyperhomocyst(e)inemias

2007 ◽  
Vol 45 (12) ◽  
Author(s):  
Rowena G. Matthews ◽  
C. Lee Elmore
Keyword(s):  
Methylenetetrahydrofolate Reductase ◽  
Minor Component ◽  
Methionine Synthase ◽  
Elevated Plasma ◽  
Wild Type ◽  
Reductase Deficiency ◽  
Methionine Synthase Reductase ◽  
A Minor ◽  
Methylenetetrahydrofolate Reductase Deficiency ◽  
Genetic Mouse Models

AbstractThere are now four genetic mouse models that induce hyperhomocyst(e)inemia by decreasing the activity of an enzyme involved in homocysteine metabolism: cystathionine β-synthase, methylenetetrahydrofolate reductase, methionine synthase and methionine synthase reductase. While each enzyme deficiency leads to murine hyperhomocyst(e)inemia, the accompanying metabolic profiles are significantly and often unexpectedly, different. Deficiencies in cystathionine β-synthase lead to elevated plasma methionine, while deficiencies of the remaining three enzymes lead to hypomethioninemia. The liver [S-adenosylmethionine]/[S-adenosylhomocysteine] ratio is decreased in mice lacking methylenetetrahydrofolate reductase or cystathionine β-synthase, but unexpectedly increased in mice with deficiencies in methionine synthase or methionine synthase reductase. Folate pool imbalances are observed in complete methylenetetrahydrofolate reductase deficiency, where methyltetra-hydrofolate is a minor component, and in methionine synthase reductase deficiency, where methyltetrahydrofolate is increased relative to wild-type mice. These differences illustrate the potential diversity among human patients with hyperhomocyst(e)inemia, and strengthen the argument that the pathologies associated with the dissimilar forms of the condition will require different treatments.Clin Chem Lab Med 2007;45:1700–3.

Role of melanotransferrin in iron metabolism: studies using targeted gene disruption in vivo

Blood ◽  
2006 ◽  
Vol 107 (7) ◽  
pp. 2599-2601 ◽  
Author(s):  
Eric O. Sekyere ◽  
Louise L. Dunn ◽  
Yohan Suryo Rahmanto ◽  
Des R. Richardson
Keyword(s):  
Metabolic Pathways ◽  
Gene Disruption ◽  
Vital Role ◽  
Plasminogen Activation ◽  
Serum Chemistry ◽  
Wild Type ◽  
Targeted Disruption ◽  
Targeted Gene Disruption

AbstractMelanotransferrin (MTf) or tumor antigen p97 is a transferrin homolog that binds one iron (Fe) atom and has been suggested to play roles in a variety of processes, including Fe metabolism, eosinophil differentiation, and plasminogen activation. Considering the vital role of Fe in many metabolic pathways, such as DNA and heme synthesis, it is important to understand the function of MTf. To define this, a MTf knockout (MTf–/–) mouse was generated through targeted disruption of the MTf gene. The MTf–/– mice were viable and fertile and developed normally, with no morphologic or histologic abnormalities. Assessment of Fe indices, tissue Fe levels, hematology, and serum chemistry parameters demonstrated no differences between MTf–/– and wild-type (MTf+/+) mice, suggesting MTf was not essential for Fe metabolism.

scholarly journals Genetics of hyperhomocysteinaemia in cardiovascular disease

2003 ◽  
Vol 40 (1) ◽  
pp. 46-59 ◽  
Author(s):  
Karin J.A. Lievers ◽  
Leo A.J. Kluijtmans ◽  
Henk J. Blom
Keyword(s):  
Cardiovascular Disease ◽  
High Plasma ◽  
Plasma Homocysteine ◽  
Genetic Defects ◽  
Vitamin B ◽  
Methionine Metabolism ◽  
Elevated Plasma ◽  
Genetic Determinants ◽  
Genes Encoding ◽  
Very High

Homocysteine, a sulphur amino acid, is a branch-point intermediate of methionine metabolism. It can be degraded in the transsulphuration pathway to cystathionine, or remethylated to methionine via the remethylation pathway. In both pathways, major genetic defects that cause enzyme deficiencies are associated with very high plasma homocysteine concentrations and excretion of homocystine into the urine. Mildly elevated plasma homocysteine concentrations are thought to be an independent and graded risk factor for both arterial occlusive disease and venous thrombosis. Genetic defects in genes encoding enzymes involved in homocysteine metabolism, or depletion of important cofactors or (co)substrates for those enzymes, including folate, vitamin B12 and vitamin B6, may result in elevated plasma homocysteine concentrations. Plasma homocysteine concentrations are also influenced by dietary and lifestyle factors. In the last decade, several studies have been conducted to elucidate the genetic determinants of hyperhomocysteinaemia in patients with cardiovascular disease. We report on both environmental and genetic determinants of hyperhomocysteinaemia and give a detailed overview of all the genetic determinants that have been reported to date.

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