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• W1994621851 abstract "A comparative study was made on the physicochemical characteristics of two isozymes of methylcobamide:- coenzyme M methyltransferase (MT2). Both isozymes catalyzed S-methylation of 2-thioethanesulfonate (coenzyme M) and exhibited similar apparent Km values for coenzyme M of 35 µM (MT2-A) and 20 µM (MT2-M). Weak binding to methylcobalamin was indicated by the apparent Km of 14 mM for both isozymes. Cob(I)alamin was established as the major product of the reaction, demonstrating heterolytic cleavage of the methylcobamide carbon-cobalt bond. The isozymes were shown to be zinc-containing metalloproteins. Metal ion chelators strongly inhibited both isozymes. A variety of coenzyme M analogs were tested for activity and/or inhibition. One alternative substrate 3-mercaptopropionate was discovered, with apparent Km 9 mM (MT2-A) and 10 mM (MT2-M). The results suggested an active site geometry in which coenzyme M is bound both by S-coordination to zinc, and electrostatic interaction of the sulfonate with a cationic group on the enzyme. Methanosarcina barkeri genes cmtA and cmtM encoding both isozymes were cloned and sequenced. Both genes encoded proteins with 339 amino acids and predicted molecular masses of 36-37 kDa. Active forms of both isozymes were expressed in Escherichia coli. A conserved segment with the potential for metal binding was found. The possibility of zinc involvement in catalysis of coenzyme M methylation is considered. A comparative study was made on the physicochemical characteristics of two isozymes of methylcobamide:- coenzyme M methyltransferase (MT2). Both isozymes catalyzed S-methylation of 2-thioethanesulfonate (coenzyme M) and exhibited similar apparent Km values for coenzyme M of 35 µM (MT2-A) and 20 µM (MT2-M). Weak binding to methylcobalamin was indicated by the apparent Km of 14 mM for both isozymes. Cob(I)alamin was established as the major product of the reaction, demonstrating heterolytic cleavage of the methylcobamide carbon-cobalt bond. The isozymes were shown to be zinc-containing metalloproteins. Metal ion chelators strongly inhibited both isozymes. A variety of coenzyme M analogs were tested for activity and/or inhibition. One alternative substrate 3-mercaptopropionate was discovered, with apparent Km 9 mM (MT2-A) and 10 mM (MT2-M). The results suggested an active site geometry in which coenzyme M is bound both by S-coordination to zinc, and electrostatic interaction of the sulfonate with a cationic group on the enzyme. Methanosarcina barkeri genes cmtA and cmtM encoding both isozymes were cloned and sequenced. Both genes encoded proteins with 339 amino acids and predicted molecular masses of 36-37 kDa. Active forms of both isozymes were expressed in Escherichia coli. A conserved segment with the potential for metal binding was found. The possibility of zinc involvement in catalysis of coenzyme M methylation is considered. INTRODUCTIONThe methanogenic archaea are able to use for growth and methanogenesis only a relatively limited number of compounds with rather simple structures (1Whitman W.B. Woese C.R. Wolfe R.S. The Bacteria. Academic Press, Inc., New York1985: 3Google Scholar, 2Ferry J.G. CRC Crit. Rev. Biochem. Mol. Biol. 1992; 27: 473-503Crossref PubMed Scopus (122) Google Scholar). These compounds include substrates containing one-carbon groups such as carbon dioxide (plus H2), formate, methanol, carbon monoxide, dimethylsulfide, and various methylated amines, as well as the two-carbon compound acetate. Growth on a three-carbon compound (pyruvate) has been observed (3Bock A.-K. Prieger-Kraft A. Schönheit P. Arch. Microbiol. 1994; 161: 33-46Google Scholar). In all methanogens the coenzyme 2-thioethanesulfonate (coenzyme M or HSCoM) 1The abbreviations used are: coenzyme M or HSCoM2-thioethanesulfonateCH3-H4SPtN5-methyl-tetrahydrosarcinapterinH4SPttetrahydrosarcinapterinmethylcoenzyme M or CH3-SCoM2-methyl-2-thioethanesulfonateMOPS3-(N-morpholino)propanesulfonic acidMT2methylcobamide:coenzyme M methyltransferaseMT1methanol: 5-hydroxybenzimidazolylcobamide methyltransferasePCRpolymerase chain reactionkbkilobase pair(s)bpbase pair(s)3-MPA3-mercaptopropanoic acid. acts as the methyl group carrier in the final step of methane formation. Methane is produced by reductive demethylation of 2-methyl-2-thioethanesulfonate (methylcoenzyme M, or CH3-SCoM) (4Wolfe R.S. Annu. Rev. Microbiol. 1991; 45: 1-35Crossref PubMed Google Scholar). Depending upon the growth substrate, different pathways lead to the production of CH3-SCoM. The pathways of methanogenesis from carbon dioxide, methanol, acetate, and pyruvate have been described in detail (3Bock A.-K. Prieger-Kraft A. Schönheit P. Arch. Microbiol. 1994; 161: 33-46Google Scholar, 5Ferry J.G. J. Bacteriol. 1992; 174: 5489-5495Crossref PubMed Scopus (150) Google Scholar, 6DiMarco A.A. Bobik T.A. Wolfe R.S. Annu. Rev. Biochem. 1990; 59: 355-394Crossref PubMed Scopus (328) Google Scholar, 7Keltjens J.T. Vogels G.D. Ferry J.G. Methanogenesis. Chapman & Hall, New York1993: 253Crossref Google Scholar). Burke and Krzycki have purified and characterized a 29-kDa corrinoid protein and shown that it functions in CH3-SCoM formation from monomethylamine (8Burke S.A. Krzycki J.A. J. Bacteriol. 1995; 177: 4410-4416Crossref PubMed Google Scholar). However, the pathways of CH3-CoM formation from this and other substrates are still not fully defined.In the conversion of methanol, synthesis of CH3-SCoM proceeds by two sequential reactions (9van der Meijden P. Heythuysen H.J. Pouwels A. Houwen F. van der Drift C. Vogels G.D. Arch. Microbiol. 1983; 134: 238-242Crossref PubMed Scopus (101) Google Scholar), as shown in Reactions 1 and 2. CH3OH+cob(I)amide-MT1+H+⇌Co-CH3cob(III)amide-MT1+H2OREACTION 1 HSCoM+Co-CH3cob(III)amide−MT1⇌cob(I)amide-MT1+CH3−SCoM+H+ REACTION 2The overall coupled reaction is given by Reaction 3. CH3OH+HSCoM⇌CH3−SCoM+H2OREACTION 3 Reaction 1 is catalyzed by the oxygen-labile enzyme methanol:5-hydroxybenzimidazolylcobamide methyltransferase (MT1) (10van der Meijden P. e Brömmelstroet B.W. Poirot C.M. van der Drift C. Vogels G.D. J. Bacteriol. 1984; 160: 629-635Crossref PubMed Google Scholar). Activation of MT1 was found to require a reducing system (H2, hydrogenase, ferredoxin), ATP, and a separate methyltransferase activator protein (10van der Meijden P. e Brömmelstroet B.W. Poirot C.M. van der Drift C. Vogels G.D. J. Bacteriol. 1984; 160: 629-635Crossref PubMed Google Scholar, 11Daas P.J.H. Gerrits K.A.A. Keltjens J.T. van der Drift C. Vogels G.D. J. Bacteriol. 1993; 175: 1278-1283Crossref PubMed Google Scholar). In Reaction 2, the enzyme methylcobamide:CoM methyltransferase (MT2) catalyzes the transfer of the methyl group from the MT1-bound methylcobamide prosthetic group to coenzyme M. The ability to catalyze Reaction 4 is used as a means for routine assay of MT2 (12Taylor C.D. Wolfe R.S. J. Biol. Chem. 1974; 249: 4886-4890Abstract Full Text PDF PubMed Google Scholar). HSCoM+methylcobalamin⇌CH3−SCoM+cob(I)alamin+H+ REACTION 4In contrast to MT1, MT2 is not inactivated by exposure to air. Hitherto, no organic or inorganic cofactors have been reported to be tightly bound to MT2. Direct evidence for the formation of cob(I)alamin as a product of the reaction has not been presented. Nevertheless, regeneration of the Co(I) form of the cobamide by heterolytic cleavage of the carbon-cobalt bond is portrayed in Reactions 2 and 4, based on results from studies on the reactivity of CH3-B12 with thiols (13Hogenkamp H.P.C. Bratt G.T. Sun S. Biochemistry. 1985; 24: 6428-6432Crossref PubMed Scopus (55) Google Scholar).Two different isoenzyme forms of MT2 (MT2-A and MT2-M) have been identified in Methanosarcina barkeri (14Grahame D.A. J. Biol. Chem. 1989; 264: 12890-12894Abstract Full Text PDF PubMed Google Scholar). Both isozymes have similar molecular masses (≈ 34 kDa, as determined by SDS-polyacrylamide gel electrophoresis), but differ in overall charge (14Grahame D.A. J. Biol. Chem. 1989; 264: 12890-12894Abstract Full Text PDF PubMed Google Scholar). The two isozymes also exhibit different chromatographic and immunological properties (14Grahame D.A. J. Biol. Chem. 1989; 264: 12890-12894Abstract Full Text PDF PubMed Google Scholar). The isoenzymes are differentially expressed depending upon the substrate available for growth (14Grahame D.A. J. Biol. Chem. 1989; 264: 12890-12894Abstract Full Text PDF PubMed Google Scholar, 15Yeliseev A. Gärtner P. Harms U. Linder D. Thauer R.K. Arch. Microbiol. 1993; 159: 530-536Crossref PubMed Scopus (33) Google Scholar). The specific metabolic functions of both isozymes were recently delineated (8Burke S.A. Krzycki J.A. J. Bacteriol. 1995; 177: 4410-4416Crossref PubMed Google Scholar, 16Ferguson D.J. Krzycki J.A. Grahame D.A. J. Biol. Chem. 1996; 271: 5189-5194Abstract Full Text PDF PubMed Scopus (61) Google Scholar). Conversions of monomethylamine and dimethylamine to CH3-SCoM are dependent upon MT2-A, and are not supported by MT2-M (8Burke S.A. Krzycki J.A. J. Bacteriol. 1995; 177: 4410-4416Crossref PubMed Google Scholar, 16Ferguson D.J. Krzycki J.A. Grahame D.A. J. Biol. Chem. 1996; 271: 5189-5194Abstract Full Text PDF PubMed Scopus (61) Google Scholar). In contrast, MT2-M acts specifically in metabolism of methanol, but does not substitute for MT2-A in conversion of monomethylamine or dimethylamine (16Ferguson D.J. Krzycki J.A. Grahame D.A. J. Biol. Chem. 1996; 271: 5189-5194Abstract Full Text PDF PubMed Scopus (61) Google Scholar). Nevertheless, both isozymes are capable of supporting the conversion of trimethylamine (16Ferguson D.J. Krzycki J.A. Grahame D.A. J. Biol. Chem. 1996; 271: 5189-5194Abstract Full Text PDF PubMed Scopus (61) Google Scholar). It is proposed that functional specificity arises as a result of protein-protein interactions between the methylated corrinoid proteins acting as methyl donor substrates and the MT2 isozyme proteins catalyzing methyl transfer to HSCoM (16Ferguson D.J. Krzycki J.A. Grahame D.A. J. Biol. Chem. 1996; 271: 5189-5194Abstract Full Text PDF PubMed Scopus (61) Google Scholar).Although cob(II)alamin was the predominant product found in nonenzymatic methyl transfer from methylcobalamin to thiols (13Hogenkamp H.P.C. Bratt G.T. Sun S. Biochemistry. 1985; 24: 6428-6432Crossref PubMed Scopus (55) Google Scholar), herein we show that cob(I)alamin is by far the major product of the reaction catalyzed by MT2. A comparative study of the physicochemical properties of the two isozymes is presented that includes determination of kinetic parameters and characterization of methyl acceptor substrate specificities. The isozymes are shown to be zinc-containing metalloproteins that are strongly inhibited by metal ion chelators. The genes encoding MT2-A and MT2-M, which we designate as cmtA and cmtM, respectively (cmt = methylcobamide:oM ethylransferase) were cloned in Escherichia coli. Furthermore, expression in E. coli is shown to produce both isozymes in an active state. Analyses of the deduced amino acid sequences of both isozymes are presented along with the tentative identification of a consensus zinc binding domain. The implications for geometric constraints on substrate binding at the active site, and the proposed function of zinc in methyltransferase catalysis are discussed. A preliminary account of this work has been presented (17LeClerc, G. M., Grahame, D. A., (1995) Ann. Meet. Am. Soc. Microbiol., May 21-25, 1995, Washington, D. C., p. 320.Google Scholar). INTRODUCTIONThe methanogenic archaea are able to use for growth and methanogenesis only a relatively limited number of compounds with rather simple structures (1Whitman W.B. Woese C.R. Wolfe R.S. The Bacteria. Academic Press, Inc., New York1985: 3Google Scholar, 2Ferry J.G. CRC Crit. Rev. Biochem. Mol. Biol. 1992; 27: 473-503Crossref PubMed Scopus (122) Google Scholar). These compounds include substrates containing one-carbon groups such as carbon dioxide (plus H2), formate, methanol, carbon monoxide, dimethylsulfide, and various methylated amines, as well as the two-carbon compound acetate. Growth on a three-carbon compound (pyruvate) has been observed (3Bock A.-K. Prieger-Kraft A. Schönheit P. Arch. Microbiol. 1994; 161: 33-46Google Scholar). In all methanogens the coenzyme 2-thioethanesulfonate (coenzyme M or HSCoM) 1The abbreviations used are: coenzyme M or HSCoM2-thioethanesulfonateCH3-H4SPtN5-methyl-tetrahydrosarcinapterinH4SPttetrahydrosarcinapterinmethylcoenzyme M or CH3-SCoM2-methyl-2-thioethanesulfonateMOPS3-(N-morpholino)propanesulfonic acidMT2methylcobamide:coenzyme M methyltransferaseMT1methanol: 5-hydroxybenzimidazolylcobamide methyltransferasePCRpolymerase chain reactionkbkilobase pair(s)bpbase pair(s)3-MPA3-mercaptopropanoic acid. acts as the methyl group carrier in the final step of methane formation. Methane is produced by reductive demethylation of 2-methyl-2-thioethanesulfonate (methylcoenzyme M, or CH3-SCoM) (4Wolfe R.S. Annu. Rev. Microbiol. 1991; 45: 1-35Crossref PubMed Google Scholar). Depending upon the growth substrate, different pathways lead to the production of CH3-SCoM. The pathways of methanogenesis from carbon dioxide, methanol, acetate, and pyruvate have been described in detail (3Bock A.-K. Prieger-Kraft A. Schönheit P. Arch. Microbiol. 1994; 161: 33-46Google Scholar, 5Ferry J.G. J. Bacteriol. 1992; 174: 5489-5495Crossref PubMed Scopus (150) Google Scholar, 6DiMarco A.A. Bobik T.A. Wolfe R.S. Annu. Rev. Biochem. 1990; 59: 355-394Crossref PubMed Scopus (328) Google Scholar, 7Keltjens J.T. Vogels G.D. Ferry J.G. Methanogenesis. Chapman & Hall, New York1993: 253Crossref Google Scholar). Burke and Krzycki have purified and characterized a 29-kDa corrinoid protein and shown that it functions in CH3-SCoM formation from monomethylamine (8Burke S.A. Krzycki J.A. J. Bacteriol. 1995; 177: 4410-4416Crossref PubMed Google Scholar). However, the pathways of CH3-CoM formation from this and other substrates are still not fully defined.In the conversion of methanol, synthesis of CH3-SCoM proceeds by two sequential reactions (9van der Meijden P. Heythuysen H.J. Pouwels A. Houwen F. van der Drift C. Vogels G.D. Arch. Microbiol. 1983; 134: 238-242Crossref PubMed Scopus (101) Google Scholar), as shown in Reactions 1 and 2. CH3OH+cob(I)amide-MT1+H+⇌Co-CH3cob(III)amide-MT1+H2OREACTION 1 HSCoM+Co-CH3cob(III)amide−MT1⇌cob(I)amide-MT1+CH3−SCoM+H+ REACTION 2The overall coupled reaction is given by Reaction 3. CH3OH+HSCoM⇌CH3−SCoM+H2OREACTION 3 Reaction 1 is catalyzed by the oxygen-labile enzyme methanol:5-hydroxybenzimidazolylcobamide methyltransferase (MT1) (10van der Meijden P. e Brömmelstroet B.W. Poirot C.M. van der Drift C. Vogels G.D. J. Bacteriol. 1984; 160: 629-635Crossref PubMed Google Scholar). Activation of MT1 was found to require a reducing system (H2, hydrogenase, ferredoxin), ATP, and a separate methyltransferase activator protein (10van der Meijden P. e Brömmelstroet B.W. Poirot C.M. van der Drift C. Vogels G.D. J. Bacteriol. 1984; 160: 629-635Crossref PubMed Google Scholar, 11Daas P.J.H. Gerrits K.A.A. Keltjens J.T. van der Drift C. Vogels G.D. J. Bacteriol. 1993; 175: 1278-1283Crossref PubMed Google Scholar). In Reaction 2, the enzyme methylcobamide:CoM methyltransferase (MT2) catalyzes the transfer of the methyl group from the MT1-bound methylcobamide prosthetic group to coenzyme M. The ability to catalyze Reaction 4 is used as a means for routine assay of MT2 (12Taylor C.D. Wolfe R.S. J. Biol. Chem. 1974; 249: 4886-4890Abstract Full Text PDF PubMed Google Scholar). HSCoM+methylcobalamin⇌CH3−SCoM+cob(I)alamin+H+ REACTION 4In contrast to MT1, MT2 is not inactivated by exposure to air. Hitherto, no organic or inorganic cofactors have been reported to be tightly bound to MT2. Direct evidence for the formation of cob(I)alamin as a product of the reaction has not been presented. Nevertheless, regeneration of the Co(I) form of the cobamide by heterolytic cleavage of the carbon-cobalt bond is portrayed in Reactions 2 and 4, based on results from studies on the reactivity of CH3-B12 with thiols (13Hogenkamp H.P.C. Bratt G.T. Sun S. Biochemistry. 1985; 24: 6428-6432Crossref PubMed Scopus (55) Google Scholar).Two different isoenzyme forms of MT2 (MT2-A and MT2-M) have been identified in Methanosarcina barkeri (14Grahame D.A. J. Biol. Chem. 1989; 264: 12890-12894Abstract Full Text PDF PubMed Google Scholar). Both isozymes have similar molecular masses (≈ 34 kDa, as determined by SDS-polyacrylamide gel electrophoresis), but differ in overall charge (14Grahame D.A. J. Biol. Chem. 1989; 264: 12890-12894Abstract Full Text PDF PubMed Google Scholar). The two isozymes also exhibit different chromatographic and immunological properties (14Grahame D.A. J. Biol. Chem. 1989; 264: 12890-12894Abstract Full Text PDF PubMed Google Scholar). The isoenzymes are differentially expressed depending upon the substrate available for growth (14Grahame D.A. J. Biol. Chem. 1989; 264: 12890-12894Abstract Full Text PDF PubMed Google Scholar, 15Yeliseev A. Gärtner P. Harms U. Linder D. Thauer R.K. Arch. Microbiol. 1993; 159: 530-536Crossref PubMed Scopus (33) Google Scholar). The specific metabolic functions of both isozymes were recently delineated (8Burke S.A. Krzycki J.A. J. Bacteriol. 1995; 177: 4410-4416Crossref PubMed Google Scholar, 16Ferguson D.J. Krzycki J.A. Grahame D.A. J. Biol. Chem. 1996; 271: 5189-5194Abstract Full Text PDF PubMed Scopus (61) Google Scholar). Conversions of monomethylamine and dimethylamine to CH3-SCoM are dependent upon MT2-A, and are not supported by MT2-M (8Burke S.A. Krzycki J.A. J. Bacteriol. 1995; 177: 4410-4416Crossref PubMed Google Scholar, 16Ferguson D.J. Krzycki J.A. Grahame D.A. J. Biol. Chem. 1996; 271: 5189-5194Abstract Full Text PDF PubMed Scopus (61) Google Scholar). In contrast, MT2-M acts specifically in metabolism of methanol, but does not substitute for MT2-A in conversion of monomethylamine or dimethylamine (16Ferguson D.J. Krzycki J.A. Grahame D.A. J. Biol. Chem. 1996; 271: 5189-5194Abstract Full Text PDF PubMed Scopus (61) Google Scholar). Nevertheless, both isozymes are capable of supporting the conversion of trimethylamine (16Ferguson D.J. Krzycki J.A. Grahame D.A. J. Biol. Chem. 1996; 271: 5189-5194Abstract Full Text PDF PubMed Scopus (61) Google Scholar). It is proposed that functional specificity arises as a result of protein-protein interactions between the methylated corrinoid proteins acting as methyl donor substrates and the MT2 isozyme proteins catalyzing methyl transfer to HSCoM (16Ferguson D.J. Krzycki J.A. Grahame D.A. J. Biol. Chem. 1996; 271: 5189-5194Abstract Full Text PDF PubMed Scopus (61) Google Scholar).Although cob(II)alamin was the predominant product found in nonenzymatic methyl transfer from methylcobalamin to thiols (13Hogenkamp H.P.C. Bratt G.T. Sun S. Biochemistry. 1985; 24: 6428-6432Crossref PubMed Scopus (55) Google Scholar), herein we show that cob(I)alamin is by far the major product of the reaction catalyzed by MT2. A comparative study of the physicochemical properties of the two isozymes is presented that includes determination of kinetic parameters and characterization of methyl acceptor substrate specificities. The isozymes are shown to be zinc-containing metalloproteins that are strongly inhibited by metal ion chelators. The genes encoding MT2-A and MT2-M, which we designate as cmtA and cmtM, respectively (cmt = methylcobamide:oM ethylransferase) were cloned in Escherichia coli. Furthermore, expression in E. coli is shown to produce both isozymes in an active state. Analyses of the deduced amino acid sequences of both isozymes are presented along with the tentative identification of a consensus zinc binding domain. The implications for geometric constraints on substrate binding at the active site, and the proposed function of zinc in methyltransferase catalysis are discussed. A preliminary account of this work has been presented (17LeClerc, G. M., Grahame, D. A., (1995) Ann. Meet. Am. Soc. Microbiol., May 21-25, 1995, Washington, D. C., p. 320.Google Scholar)." @default.
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• W1994621851 title "Methylcobamide:Coenzyme M Methyltransferase Isozymes from Methanosarcina barkeri" @default.
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