Methylmalonyl-CoA epimerase (MMCE); MMCE, also called methylmalonyl-CoA racemase (EC 5.1.99.1) interconverts (2R)-methylmalonyl-CoA and (2S)-methylmalonyl-CoA. MMCE has been found in bacteria, archaea, and in animals. In eukaryotes, MMCE is an essential enzyme in a pathway that converts propionyl-CoA to succinyl-CoA, and is important in the breakdown of odd-chain length fatty acids, branched-chain amino acids, and other metabolites. In bacteria, MMCE participates in the reverse pathway for propionate fermentation, glyoxylate regeneration, and the biosynthesis of polyketide antibiotics. MMCE is closely related to glyoxalase I and type I extradiol dioxygenases.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17506387  35 LNHVAIATPDLKKSSEFYKG-LGAKVSEAVPQPEHGVYTVFVELPNSKIELLHPFGEKSPIQAFLnKNKDGGMHHICIEV 113
Cdd:cd07249   1 LDHIGIAVPDLDEALKFYEDvLGVKVSEPEELEEQGVRVAFLELGNTQIELLEPLGEDSPIAKFL-DKKGGGLHHIAFEV 79

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*...
gi 17506387 114 RDIHEAVSAVKTKGIRTLGEKPKIGAHGKEVMFLHPKDCGGVLIELEQ 161
Cdd:cd07249  80 DDIDAAVEELKAQGVRLLSEGPRIGAHGKRVAFLHPKDTGGVLIELVE 127

Glyoxalase/Bleomycin resistance protein/Dioxygenase superfamily;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17506387    36 NHVAIATPDLKKSSEFYKG-LGAKVSEAVPQPEHGVYTVFVELPNS--KIELLHPFGEKSPIqaflnKNKDGGMHHICIE 112
Cdd:pfam13669   1 HHVGIAVPDLDRALALWGAlLGLGPEGDYRSEPQNVDLAFALLGDGpvEVELIQPLDGDSPL-----ARHGPGLHHLAYW 75

                          90       100       110
                  ....*....|....*....|....*....|....
gi 17506387   113 VRDIHEAVSAVKTKGIRTLGEKPKIGAHGKEVMF 146
Cdd:pfam13669  76 VDDLDAAVARLLDQGYRVAPKGPRAGAAGRRVAF 109

Methylmalonyl-CoA epimerase (MMCE); MMCE, also called methylmalonyl-CoA racemase (EC 5.1.99.1) interconverts (2R)-methylmalonyl-CoA and (2S)-methylmalonyl-CoA. MMCE has been found in bacteria, archaea, and in animals. In eukaryotes, MMCE is an essential enzyme in a pathway that converts propionyl-CoA to succinyl-CoA, and is important in the breakdown of odd-chain length fatty acids, branched-chain amino acids, and other metabolites. In bacteria, MMCE participates in the reverse pathway for propionate fermentation, glyoxylate regeneration, and the biosynthesis of polyketide antibiotics. MMCE is closely related to glyoxalase I and type I extradiol dioxygenases.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17506387  35 LNHVAIATPDLKKSSEFYKG-LGAKVSEAVPQPEHGVYTVFVELPNSKIELLHPFGEKSPIQAFLnKNKDGGMHHICIEV 113
Cdd:cd07249   1 LDHIGIAVPDLDEALKFYEDvLGVKVSEPEELEEQGVRVAFLELGNTQIELLEPLGEDSPIAKFL-DKKGGGLHHIAFEV 79

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*...
gi 17506387 114 RDIHEAVSAVKTKGIRTLGEKPKIGAHGKEVMFLHPKDCGGVLIELEQ 161
Cdd:cd07249  80 DDIDAAVEELKAQGVRLLSEGPRIGAHGKRVAFLHPKDTGGVLIELVE 127

Catechol 2,3-dioxygenase or related enzyme, vicinal oxygen chelate (VOC) family [Secondary metabolites biosynthesis, transport and catabolism];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17506387  34 KLNHVAIATPDLKKSSEFYKG-LGAKVSEAVPQPEHGVYTVFVELPN-SKIELLHPFGEKSpiqaflnKNKDGGMHHICI 111
Cdd:COG0346   2 GLHHVTLRVSDLEASLAFYTDvLGLELVKRTDFGDGGFGHAFLRLGDgTELELFEAPGAAP-------APGGGGLHHLAF 74

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*...
gi 17506387 112 EVRDIHEAVSAVKTKGIRTLGEkPKIGAHGKEVMFLhpKDCGGVLIEL 159
Cdd:COG0346  75 RVDDLDAAYARLRAAGVEIEGE-PRDRAYGYRSAYF--RDPDGNLIEL 119

Glyoxalase/Bleomycin resistance protein/Dioxygenase superfamily;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17506387    34 KLNHVAIATPDLKKSSEFY-KGLGAKVSEAVPQPEHGVYTVFVELPNS-KIELLHPFGEKSPIqaflNKNKDGGMHHICI 111
Cdd:pfam00903   1 RIDHVALRVGDLEKSLDFYtDVLGFKLVEETDAGEEGGLRSAFFLAGGrVLELLLNETPPPAA----AGFGGHHIAFIAF 76

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 17506387   112 EVRDIHEAVSAVKTKGIRTLGEkpkIGAHGKEVMFLHPKDCGGVLIEL 159
Cdd:pfam00903  77 SVDDVDAAYDRLKAAGVEIVRE---PGRHGWGGRYSYFRDPDGNLIEL 121

vicinal oxygen chelate (VOC) family; The vicinal oxygen chelate (VOC) superfamily is composed of structurally related proteins with paired beta.alpha.beta.beta.beta motifs that provide a metal coordination environment with two or three open or readily accessible coordination sites to promote direct electrophilic participation of the metal ion in catalysis. VOC is found in a variety of structurally related metalloproteins, including the type I extradiol dioxygenases, glyoxalase I and a group of antibiotic resistance proteins. A bound metal ion is required for protein activities for the members of this superfamily. A variety of metal ions have been found in the catalytic centers of these proteins including Fe(II), Mn(II), Zn(II), Ni(II) and Mg(II). Type I extradiol dioxygenases catalyze the incorporation of both atoms of molecular oxygen into aromatic substrates, which results in the cleavage of aromatic rings. They are key enzymes in the degradation of aromatic compounds. Type I extradiol dioxygenases include class I and class II enzymes. Class I and II enzymes show sequence similarity; the two-domain class II enzymes evolved from a class I enzyme through gene duplication. Glyoxylase I catalyzes the glutathione-dependent inactivation of toxic methylglyoxal, requiring zinc or nickel ions for activity. The antibiotic resistance proteins in this family use a variety of mechanisms to block the function of antibiotics. Bleomycin resistance protein (BLMA) sequesters bleomycin's activity by directly binding to it. Whereas, three types of fosfomycin resistance proteins employ different mechanisms to render fosfomycin inactive by modifying the fosfomycin molecule. Although the proteins in this superfamily are functionally distinct, their structures are similar. The difference among the three dimensional structures of the three types of proteins in this superfamily is interesting from an evolutionary perspective. Both glyoxalase I and BLMA show domain swapping between subunits. However, there is no domain swapping for type 1 extradiol dioxygenases.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17506387  37 HVAIATPDLKKSSEFY-KGLGAKVseaVPQPEHGVYTVFVELPNSKIELLHPFGEKSPiqaflnknKDGGMHHICIEVRD 115
Cdd:cd06587   1 HVALRVPDLDASVAFYeEVLGFEV---VSRNEGGGFAFLRLGPGLRLALLEGPEPERP--------GGGGLFHLAFEVDD 69

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*
gi 17506387 116 IHEAVSAVKTKGIRTLGEKPKIGAH-GKEVMFLHpkDCGGVLIEL 159
Cdd:cd06587  70 VDEVDERLREAGAEGELVAPPVDDPwGGRSFYFR--DPDGNLIEF 112

Glyoxalase I that uses Ni(++) as cofactor; This family includes Escherichia coil and other prokaryotic glyoxalase I that uses nickel as cofactor. Glyoxalase I (also known as lactoylglutathione lyase; EC 4.4.1.5) is part of the glyoxalase system, a two-step system for detoxifying methylglyoxal, a side product of glycolysis. This system is responsible for the conversion of reactive, acyclic alpha-oxoaldehydes into the corresponding alpha-hydroxyacids and involves 2 enzymes, glyoxalase I and II. Glyoxalase I catalyses an intramolecular redox reaction of the hemithioacetal (formed from methylglyoxal and glutathione) to form the thioester, S-D-lactoylglutathione. This reaction involves the transfer of two hydrogen atoms from C1 to C2 of the methylglyoxal, and proceeds via an ene-diol intermediate. Glyoxalase I has a requirement for bound metal ions for catalysis. Eukaryotic glyoxalase I prefers the divalent cation zinc as cofactor, whereas Escherichia coil and other prokaryotic glyoxalase I uses nickel. However, eukaryotic Trypanosomatid parasites also use nickel as a cofactor, which could possibly be explained by acquiring their GLOI gene by horizontal gene transfer. Human glyoxalase I is a two-domain enzyme and it has the structure of a domain-swapped dimer with two active sites located at the dimer interface. In yeast, in various plants, insects and Plasmodia, glyoxalase I is four-domain, possibly the result of a further gene duplication and an additional gene fusing event.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17506387  37 HVAIATPDLKKSSEFY-KGLGAKVSEAVPQPEhGVYT-VFV----ELPNSKIELLHPFGEKSpiqaflnKNKDGGMHHIC 110
Cdd:cd16358   3 HTMLRVGDLDRSIKFYtEVLGMKLLRKRDYPE-GKYTlAFVgygdEDENTVLELTYNWGVDK-------YDLGTAYGHIA 74

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
gi 17506387 111 IEVRDIHEAVSAVKTKGIRTLGEkPKIGAHGKEVM-FLHPKDcgGVLIEL 159
Cdd:cd16358  75 IGVEDVYETCERIRKKGGKVTRE-PGPMKGGTTVIaFVEDPD--GYKIEL 121

Glyoxalase I that uses Zn(++) as cofactor; This family includes eukaryotic glyoxalase I that prefers the divalent cation zinc as cofactor. Glyoxalase I (also known as lactoylglutathione lyase; EC 4.4.1.5) is part of the glyoxalase system, a two-step system for detoxifying methylglyoxal, a side product of glycolysis. This system is responsible for the conversion of reactive, acyclic alpha-oxoaldehydes into the corresponding alpha-hydroxyacids and involves 2 enzymes, glyoxalase I and II. Glyoxalase I catalyses an intramolecular redox reaction of the hemithioacetal (formed from methylglyoxal and glutathione) to form the thioester, S-D-lactoylglutathione. This reaction involves the transfer of two hydrogen atoms from C1 to C2 of the methylglyoxal, and proceeds via an ene-diol intermediate. Glyoxalase I has a requirement for bound metal ions for catalysis. Eukaryotic glyoxalase I prefers the divalent cation zinc as cofactor, whereas Escherichia coil and other prokaryotic glyoxalase I uses nickel. However, eukaryotic Trypanosomatid parasites also use nickel as a cofactor, which could possibly be explained by acquiring their GLOI gene by horizontal gene transfer. Human glyoxalase I is a two-domain enzyme and it has the structure of a domain-swapped dimer with two active sites located at the dimer interface. In yeast, in various plants, insects and Plasmodia, glyoxalase I is four-domain, possibly the result of a further gene duplication and an additional gene fusing event.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17506387  35 LNHVAIATPDLKKSSEFYKG-LGAKV-----------------SEAVPQPEHGVYTVFVELPNSKIELLHPFG-EKSPIQ 95
Cdd:cd07233   1 FNHTMLRVKDPKKSLKFYTEvLGMKLlrkkdfpemkfslyflgYEDPKDIPKDPRTAWVFSREGTLELTHNWGtENDEDP 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 17506387  96 AFLNKNKDG-GMHHICIEVRDIHEAVSAVKTKGIrTLGEKPKIGAHgKEVMFLhpKDCGGVLIEL 159
Cdd:cd07233  81 VYHNGNSDPrGFGHIGIAVDDVYAACERFEELGV-KFKKKPDDGKM-KGIAFI--KDPDGYWIEI 141

Catechol-2,3-dioxygenase [Secondary metabolites biosynthesis, transport and catabolism];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17506387  34 KLNHVAIATPDLKKSSEFYKG-LGAKVSEAVPQpehgvyTVFVELPNSKIEL-LHPFGEKSPIQAflnknkDGGMHHICI 111
Cdd:COG2514   3 RLGHVTLRVRDLERSAAFYTDvLGLEVVEREGG------RVYLRADGGEHLLvLEEAPGAPPRPG------AAGLDHVAF 70

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|.
gi 17506387 112 EVR---DIHEAVSAVKTKGIRTLGEKPkiGAHGKEVMFLHPkdcGGVLIEL 159
Cdd:COG2514  71 RVPsraDLDAALARLAAAGVPVEGAVD--HGVGESLYFRDP---DGNLIEL 116

C-terminal domain of type I, class II extradiol dioxygenases, catalytic domain; This family contains the C-terminal, catalytic domain of type I, class II extradiol dioxygenases. Dioxygenases catalyze the incorporation of both atoms of molecular oxygen into substrates using a variety of reaction mechanisms, resulting in the cleavage of aromatic rings. Two major groups of dioxygenases have been identified according to the cleavage site; extradiol enzymes cleave the aromatic ring between a hydroxylated carbon and an adjacent non-hydroxylated carbon, whereas intradiol enzymes cleave the aromatic ring between two hydroxyl groups. Extradiol dioxygenases are classified into type I and type II enzymes. Type I extradiol dioxygenases include class I and class II enzymes. These two classes of enzymes show sequence similarity; the two-domain class II enzymes evolved from a class I enzyme through gene duplication. The extradiol dioxygenases represented in this family are type I, class II enzymes, and are composed of the N- and C-terminal domains of similar structure fold, resulting from an ancient gene duplication. The active site is located in a funnel-shaped space of the C-terminal domain. A catalytically essential metal, Fe(II) or Mn(II), presents in all the enzymes in this family.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17506387  37 HVAIATPDLKKSSEFY-KGLGAKVSEAVPQPEHGVyTVFVELpnSKIELLHPFgekspiqaFLNKNKDGGMHHICIEVRD 115
Cdd:cd08343   2 HVVLCSPDVEASRDFYtDVLGFRVSDRIVDPGVDG-GAFLHC--DRGTDHHTV--------ALAGGPHPGLHHVAFEVHD 70

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
gi 17506387 116 IHEAVsavktKGIRTLGEK-PKI----GAHGKEVM-FLHPKDCGGVLIEL 159
Cdd:cd08343  71 LDDVG-----RGHDRLREKgYKIewgpGRHGLGSQvFDYWFDPSGNRVEY 115

C-terminal domain of 4-hydroxyphenylpyruvate dioxygenase (HppD) and hydroxymandelate synthase (HmaS); HppD and HmaS are non-heme iron-dependent dioxygenases, which modify a common substrate, 4-hydroxyphenylpyruvate (HPP), but yield different products. HPPD catalyzes the second reaction in tyrosine catabolism, the conversion of 4-hydroxyphenylpyruvate to homogentisate (2,5-dihydroxyphenylacetic acid, HG). HmaS converts HPP to 4-hydroxymandelate, a committed step in the formation of hydroxyphenylglycerine, a structural component of nonproteinogenic macrocyclic peptide antibiotics, such as vancomycin. If the emphasis is on catalytic chemistry, HPPD and HmaS are classified as members of a large family of alpha-keto acid dependent mononuclear non-heme iron oxygenases most of which require Fe(II), molecular oxygen, and an alpha-keto acid (typically alpha-ketoglutarate) to either oxygenate or oxidize a third substrate. Both enzymes are exceptions in that they require two, instead of three, substrates, do not use alpha-ketoglutarate, and incorporate both atoms of dioxygen into the aromatic product. Both HPPD and HmaS exhibit duplicate beta barrel topology in their N- and C-terminal domains which share sequence similarity, suggestive of a gene duplication. Each protein has only one catalytic site located in at the C-terminal domain. This HPPD_C_like domain represents the C-terminal domain.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17506387  37 HVAIATPD--LKKSSEFYKG-LGAK-----VSEAVPQPEHGVYTVFVELPNSKIELlhPFGE------KSPIQAFLNKNK 102
Cdd:cd07250   6 HVVGNVPDgeMDPAVEWYEKcLGFHrfwefDDEDIGTEYSGLRSIVLANPNETIKL--PLNEpapgkrKSQIQEFLDYHG 83

                        90       100
                ....*....|....*....|....*....
gi 17506387 103 DGGMHHICIEVRDIHEAVSAVKTKGIRTL 131
Cdd:cd07250  84 GAGVQHIALNTDDIFATVRALRARGVEFL 112