beta-ketoacyl reductase (KR) domain of fatty acid synthase (FAS), subgroup 1, complex (x) SDRs; NADP-dependent KR domain of the multidomain type I FAS, a complex SDR family. This subfamily also includes proteins identified as polyketide synthase (PKS), a protein with related modular protein architecture and similar function. It includes the KR domains of mammalian and chicken FAS, and Dictyostelium discoideum putative polyketide synthases (PKSs). These KR domains contain two subdomains, each of which is related to SDR Rossmann fold domains. However, while the C-terminal subdomain has an active site similar to the other SDRs and a NADP-binding capability, the N-terminal SDR-like subdomain is truncated and lacks these functions, serving a supportive structural role. In some instances, such as porcine FAS, an enoyl reductase (a Rossman fold NAD-binding domain of the medium-chain dehydrogenase/reductase, MDR family) module is inserted between the sub-domains. Fatty acid synthesis occurs via the stepwise elongation of a chain (which is attached to acyl carrier protein, ACP) with 2-carbon units. Eukaryotic systems consists of large, multifunctional synthases (type I) while bacterial, type II systems, use single function proteins. Fungal fatty acid synthesis uses a dodecamer of 6 alpha and 6 beta subunits. In mammalian type FAS cycles, ketoacyl synthase forms acetoacetyl-ACP which is reduced by the NADP-dependent beta-ketoacyl reductase (KR), forming beta-hydroxyacyl-ACP, which is in turn dehydrated by dehydratase to a beta-enoyl intermediate, which is reduced by NADP-dependent beta-enoyl reductase (ER); this KR and ER are members of the SDR family. This KR subfamily has an active site tetrad with a similar 3D orientation compared to archetypical SDRs, but the active site Lys and Asn residue positions are swapped. The characteristic NADP-binding is typical of the multidomain complex SDRs, with a GGXGXXG NADP binding motif. SDRs are a functionally diverse family of oxidoreductases that have a single domain with a structurally conserved Rossmann fold (alpha/beta folding pattern with a central beta-sheet), an NAD(P)(H)-binding region, and a structurally diverse C-terminal region. Classical SDRs are typically about 250 residues long, while extended SDRs are approximately 350 residues. Sequence identity between different SDR enzymes are typically in the 15-30% range, but the enzymes share the Rossmann fold NAD-binding motif and characteristic NAD-binding and catalytic sequence patterns. These enzymes catalyze a wide range of activities including the metabolism of steroids, cofactors, carbohydrates, lipids, aromatic compounds, and amino acids, and act in redox sensing. Classical SDRs have an TGXXX[AG]XG cofactor binding motif and a YXXXK active site motif, with the Tyr residue of the active site motif serving as a critical catalytic residue (Tyr-151, human prostaglandin dehydrogenase (PGDH) numbering). In addition to the Tyr and Lys, there is often an upstream Ser (Ser-138, PGDH numbering) and/or an Asn (Asn-107, PGDH numbering) contributing to the active site; while substrate binding is in the C-terminal region, which determines specificity. The standard reaction mechanism is a 4-pro-S hydride transfer and proton relay involving the conserved Tyr and Lys, a water molecule stabilized by Asn, and nicotinamide. Extended SDRs have additional elements in the C-terminal region, and typically have a TGXXGXXG cofactor binding motif. Complex (multidomain) SDRs such as ketoreductase domains of fatty acid synthase have a GGXGXXG NAD(P)-binding motif and an altered active site motif (YXXXN). Fungal type KRs have a TGXXXGX(1-2)G NAD(P)-binding motif. Some atypical SDRs have lost catalytic activity and/or have an unusual NAD(P)-binding motif and missing or unusual active site residues. Reactions catalyzed within the SDR family include isomerization, decarboxylation, epimerization, C=N bond reduction, dehydratase activity, dehalogenation, Enoyl-CoA reduction, and carbonyl-alcohol oxidoreduction.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 222 NCAVAALGDPASalSNMVAALREGGFLLLHTLLRGHPLGDIVAFlTSTEPQYGQGILSQDAWESLFS---RVSLRLVGLK 298
Cdd:cd08954   5 VCNLVLNGNLQS--ENLYALLKPNGFLLFVEPLKGSTLGDTWWL-TDNDIRKQSCLLSQEQWNQLLKstqEVSIKLSGVK 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 299 KSFYGSTLflCRRPTPQDSPIFLPVDDTSFRWVESLKGILADEdSSRPVWLKAINCATSGVVGLVNCLRREPGGNRLRCV 378
Cdd:cd08954  82 KSFYGSVL--CRIQSPTDKSEFLPVEEQTFEYVEILKSLLATA-SCKPVLLTADGCESSGVIGAVRYFREEPQLKLIRCL 158

                       170       180       190       200       210
                ....*....|....*....|....*....|....*....|....*....|
gi 38196957 379 LLSNLSSTSHvPEVDPGSAELQKVLQGDLVMNVYRDGAWGAFRHFLLEED 428
Cdd:cd08954 159 FVSNLNSQKE-PIIRNGKVYYERVKKNSNIKNVYKSGSWGDFRHLLLDLS 207

enoyl reductase of polyketide synthase; Putative enoyl reductase of polyketide synthase. Polyketide synthases produce polyketides in step by step mechanism that is similar to fatty acid synthesis. Enoyl reductase reduces a double to single bond. Erythromycin is one example of a polyketide generated by 3 complex enzymes (megasynthases). 2-enoyl thioester reductase (ETR) catalyzes the NADPH-dependent dependent conversion of trans-2-enoyl acyl carrier protein/coenzyme A (ACP/CoA) to acyl-(ACP/CoA) in fatty acid synthesis. 2-enoyl thioester reductase activity has been linked in Candida tropicalis as essential in maintaining mitiochondrial respiratory function. This ETR family is a part of the medium chain dehydrogenase/reductase family, but lack the zinc coordination sites characteristic of the alcohol dehydrogenases in this family. NAD(P)(H)-dependent oxidoreductases are the major enzymes in the interconversion of alcohols and aldehydes or ketones. Alcohol dehydrogenase in the liver converts ethanol and NAD+ to acetaldehyde and NADH, while in yeast and some other microorganisms ADH catalyzes the conversion acetaldehyde to ethanol in alcoholic fermentation. ADH is a member of the medium chain alcohol dehydrogenase family (MDR), which has a NAD(P)(H)-binding domain in a Rossmann fold of a beta-alpha form. The NAD(H)-binding region is comprised of 2 structurally similar halves, each of which contacts a mononucleotide. The N-terminal catalytic domain has a distant homology to GroES. These proteins typically form dimers (typically higher plants, mammals) or tetramers (yeast, bacteria), and have 2 tightly bound zinc atoms per subunit, a catalytic zinc at the active site, and a structural zinc in a lobe of the catalytic domain. NAD(H) binding occurs in the cleft between the catalytic and coenzyme-binding domains, at the active site, and coenzyme binding induces a conformational closing of this cleft. Coenzyme binding typically precedes and contributes to substrate binding.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 472 VYYASLNFRDIMLATGKLSPDaipgkwtsqDSLLGMEFSGRD----------ASGKRVMGLVPaKGLATSVLLSPDFLWD 541
Cdd:cd05195   7 VKAAGLNFRDVLVALGLLPGD---------ETPLGLECSGIVtrvgsgvtglKVGDRVMGLAP-GAFATHVRVDARLVVK 76

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 542 VPSNWTLEEAASVPVVYSTAYYALVVRGRVRPGETLLIHSGSGGVGQAAIAIALSLGCRVFTTVGSAEKRAYLQARFPql 621
Cdd:cd05195  77 IPDSLSFEEAATLPVAYLTAYYALVDLARLQKGESVLIHAAAGGVGQAAIQLAQHLGAEVFATVGSEEKREFLRELGG-- 154

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 622 DSTSFANSRDTSFEQHVLWHTGGKGVDLVLNSLAEEKLQASVRCLATHGRFLEIGKFDLSQNHPLGMAIFLKNVTFHGVL 701
Cdd:cd05195 155 PVDHIFSSRDLSFADGILRATGGRGVDVVLNSLSGELLRASWRCLAPFGRFVEIGKRDILSNSKLGMRPFLRNVSFSSVD 234

                       250       260       270       280       290
                ....*....|....*....|....*....|....*....|....*....|..
gi 38196957 702 LDAFFNESSADWREVWALVQAGIRDGVVRPLKCTVFHGAQVEDAFRYMAQGK 753
Cdd:cd05195 235 LDQLARERPELLRELLREVLELLEAGVLKPLPPTVVPSASEIDAFRLMQSGK 286

beta-ketoacyl reductase (KR) domain of fatty acid synthase (FAS), subgroup 1, complex (x) SDRs; NADP-dependent KR domain of the multidomain type I FAS, a complex SDR family. This subfamily also includes proteins identified as polyketide synthase (PKS), a protein with related modular protein architecture and similar function. It includes the KR domains of mammalian and chicken FAS, and Dictyostelium discoideum putative polyketide synthases (PKSs). These KR domains contain two subdomains, each of which is related to SDR Rossmann fold domains. However, while the C-terminal subdomain has an active site similar to the other SDRs and a NADP-binding capability, the N-terminal SDR-like subdomain is truncated and lacks these functions, serving a supportive structural role. In some instances, such as porcine FAS, an enoyl reductase (a Rossman fold NAD-binding domain of the medium-chain dehydrogenase/reductase, MDR family) module is inserted between the sub-domains. Fatty acid synthesis occurs via the stepwise elongation of a chain (which is attached to acyl carrier protein, ACP) with 2-carbon units. Eukaryotic systems consists of large, multifunctional synthases (type I) while bacterial, type II systems, use single function proteins. Fungal fatty acid synthesis uses a dodecamer of 6 alpha and 6 beta subunits. In mammalian type FAS cycles, ketoacyl synthase forms acetoacetyl-ACP which is reduced by the NADP-dependent beta-ketoacyl reductase (KR), forming beta-hydroxyacyl-ACP, which is in turn dehydrated by dehydratase to a beta-enoyl intermediate, which is reduced by NADP-dependent beta-enoyl reductase (ER); this KR and ER are members of the SDR family. This KR subfamily has an active site tetrad with a similar 3D orientation compared to archetypical SDRs, but the active site Lys and Asn residue positions are swapped. The characteristic NADP-binding is typical of the multidomain complex SDRs, with a GGXGXXG NADP binding motif. SDRs are a functionally diverse family of oxidoreductases that have a single domain with a structurally conserved Rossmann fold (alpha/beta folding pattern with a central beta-sheet), an NAD(P)(H)-binding region, and a structurally diverse C-terminal region. Classical SDRs are typically about 250 residues long, while extended SDRs are approximately 350 residues. Sequence identity between different SDR enzymes are typically in the 15-30% range, but the enzymes share the Rossmann fold NAD-binding motif and characteristic NAD-binding and catalytic sequence patterns. These enzymes catalyze a wide range of activities including the metabolism of steroids, cofactors, carbohydrates, lipids, aromatic compounds, and amino acids, and act in redox sensing. Classical SDRs have an TGXXX[AG]XG cofactor binding motif and a YXXXK active site motif, with the Tyr residue of the active site motif serving as a critical catalytic residue (Tyr-151, human prostaglandin dehydrogenase (PGDH) numbering). In addition to the Tyr and Lys, there is often an upstream Ser (Ser-138, PGDH numbering) and/or an Asn (Asn-107, PGDH numbering) contributing to the active site; while substrate binding is in the C-terminal region, which determines specificity. The standard reaction mechanism is a 4-pro-S hydride transfer and proton relay involving the conserved Tyr and Lys, a water molecule stabilized by Asn, and nicotinamide. Extended SDRs have additional elements in the C-terminal region, and typically have a TGXXGXXG cofactor binding motif. Complex (multidomain) SDRs such as ketoreductase domains of fatty acid synthase have a GGXGXXG NAD(P)-binding motif and an altered active site motif (YXXXN). Fungal type KRs have a TGXXXGX(1-2)G NAD(P)-binding motif. Some atypical SDRs have lost catalytic activity and/or have an unusual NAD(P)-binding motif and missing or unusual active site residues. Reactions catalyzed within the SDR family include isomerization, decarboxylation, epimerization, C=N bond reduction, dehydratase activity, dehalogenation, Enoyl-CoA reduction, and carbonyl-alcohol oxidoreduction.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 222 NCAVAALGDPASalSNMVAALREGGFLLLHTLLRGHPLGDIVAFlTSTEPQYGQGILSQDAWESLFS---RVSLRLVGLK 298
Cdd:cd08954   5 VCNLVLNGNLQS--ENLYALLKPNGFLLFVEPLKGSTLGDTWWL-TDNDIRKQSCLLSQEQWNQLLKstqEVSIKLSGVK 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 299 KSFYGSTLflCRRPTPQDSPIFLPVDDTSFRWVESLKGILADEdSSRPVWLKAINCATSGVVGLVNCLRREPGGNRLRCV 378
Cdd:cd08954  82 KSFYGSVL--CRIQSPTDKSEFLPVEEQTFEYVEILKSLLATA-SCKPVLLTADGCESSGVIGAVRYFREEPQLKLIRCL 158

                       170       180       190       200       210
                ....*....|....*....|....*....|....*....|....*....|
gi 38196957 379 LLSNLSSTSHvPEVDPGSAELQKVLQGDLVMNVYRDGAWGAFRHFLLEED 428
Cdd:cd08954 159 FVSNLNSQKE-PIIRNGKVYYERVKKNSNIKNVYKSGSWGDFRHLLLDLS 207

alcohol dehydrogenase; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957  469 LCTVYYASLNFRDIMLATGKLSPDaiPGkwtsQDSLLGMEFSG----------RDASGKRVMGLVPAKGLATSVLLSPDF 538
Cdd:PTZ00354  32 LIKVSAAGVNRADTLQRQGKYPPP--PG----SSEILGLEVAGyvedvgsdvkRFKEGDRVMALLPGGGYAEYAVAHKGH 105

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957  539 LWDVPSNWTLEEAASVPVVYSTAYYALVVRGRVRPGETLLIHSGSGGVGQAAIAIALSLGCRVFTTVGSAEKRAYLQarf 618
Cdd:PTZ00354 106 VMHIPQGYTFEEAAAIPEAFLTAWQLLKKHGDVKKGQSVLIHAGASGVGTAAAQLAEKYGAATIITTSSEEKVDFCK--- 182

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 38196957  619 pQLDSTSFANSRD-TSFEQHVLWHTGGKGVDLVLNSLAEEKLQASVRCLATHGRFLEIG 676
Cdd:PTZ00354 183 -KLAAIILIRYPDeEGFAPKVKKLTGEKGVNLVLDCVGGSYLSETAEVLAVDGKWIVYG 240

Methyltransferase domain; Members of this family are SAM dependent methyltransferases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957   149 VEVLAGHGHLYSRIPGLLSphpllQLSYTATDRHPQALEAAQAELQQ---HDVAQGQWDPADPAPSALGSADLLVCNCAV 225
Cdd:pfam08242   1 LEIGCGTGTLLRALLEALP-----GLEYTGLDISPAALEAARERLAAlglLNAVRVELFQLDLGELDPGSFDVVVASNVL 75

                          90       100
                  ....*....|....*....|...
gi 38196957   226 AALGDPASALSNMVAALREGGFL 248
Cdd:pfam08242  76 HHLADPRAVLRNIRRLLKPGGVL 98

2-polyprenyl-3-methyl-5-hydroxy-6-metoxy-1,4-benzoquinol methylase [Coenzyme transport and metabolism]; 2-polyprenyl-3-methyl-5-hydroxy-6-metoxy-1,4-benzoquinol methylase is part of the Pathway/BioSystem: Ubiquinone biosynthesis

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 38196957 175 SYTATDRHPQALEAAQAELQQHDVAQGQWDpADPAPSALGSADLLVCNCAVAALGDPASALSNMVAALREGGFLLLHT 252
Cdd:COG2227  48 DVTGVDISPEALEIARERAAELNVDFVQGD-LEDLPLEDGSFDLVICSEVLEHLPDPAALLRELARLLKPGGLLLLST 124

enoyl reductase of polyketide synthase; Putative enoyl reductase of polyketide synthase. Polyketide synthases produce polyketides in step by step mechanism that is similar to fatty acid synthesis. Enoyl reductase reduces a double to single bond. Erythromycin is one example of a polyketide generated by 3 complex enzymes (megasynthases). 2-enoyl thioester reductase (ETR) catalyzes the NADPH-dependent dependent conversion of trans-2-enoyl acyl carrier protein/coenzyme A (ACP/CoA) to acyl-(ACP/CoA) in fatty acid synthesis. 2-enoyl thioester reductase activity has been linked in Candida tropicalis as essential in maintaining mitiochondrial respiratory function. This ETR family is a part of the medium chain dehydrogenase/reductase family, but lack the zinc coordination sites characteristic of the alcohol dehydrogenases in this family. NAD(P)(H)-dependent oxidoreductases are the major enzymes in the interconversion of alcohols and aldehydes or ketones. Alcohol dehydrogenase in the liver converts ethanol and NAD+ to acetaldehyde and NADH, while in yeast and some other microorganisms ADH catalyzes the conversion acetaldehyde to ethanol in alcoholic fermentation. ADH is a member of the medium chain alcohol dehydrogenase family (MDR), which has a NAD(P)(H)-binding domain in a Rossmann fold of a beta-alpha form. The NAD(H)-binding region is comprised of 2 structurally similar halves, each of which contacts a mononucleotide. The N-terminal catalytic domain has a distant homology to GroES. These proteins typically form dimers (typically higher plants, mammals) or tetramers (yeast, bacteria), and have 2 tightly bound zinc atoms per subunit, a catalytic zinc at the active site, and a structural zinc in a lobe of the catalytic domain. NAD(H) binding occurs in the cleft between the catalytic and coenzyme-binding domains, at the active site, and coenzyme binding induces a conformational closing of this cleft. Coenzyme binding typically precedes and contributes to substrate binding.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 472 VYYASLNFRDIMLATGKLSPDaipgkwtsqDSLLGMEFSGRD----------ASGKRVMGLVPaKGLATSVLLSPDFLWD 541
Cdd:cd05195   7 VKAAGLNFRDVLVALGLLPGD---------ETPLGLECSGIVtrvgsgvtglKVGDRVMGLAP-GAFATHVRVDARLVVK 76

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 542 VPSNWTLEEAASVPVVYSTAYYALVVRGRVRPGETLLIHSGSGGVGQAAIAIALSLGCRVFTTVGSAEKRAYLQARFPql 621
Cdd:cd05195  77 IPDSLSFEEAATLPVAYLTAYYALVDLARLQKGESVLIHAAAGGVGQAAIQLAQHLGAEVFATVGSEEKREFLRELGG-- 154

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 622 DSTSFANSRDTSFEQHVLWHTGGKGVDLVLNSLAEEKLQASVRCLATHGRFLEIGKFDLSQNHPLGMAIFLKNVTFHGVL 701
Cdd:cd05195 155 PVDHIFSSRDLSFADGILRATGGRGVDVVLNSLSGELLRASWRCLAPFGRFVEIGKRDILSNSKLGMRPFLRNVSFSSVD 234

                       250       260       270       280       290
                ....*....|....*....|....*....|....*....|....*....|..
gi 38196957 702 LDAFFNESSADWREVWALVQAGIRDGVVRPLKCTVFHGAQVEDAFRYMAQGK 753
Cdd:cd05195 235 LDQLARERPELLRELLREVLELLEAGVLKPLPPTVVPSASEIDAFRLMQSGK 286

Quinone oxidoreductase (QOR); QOR catalyzes the conversion of a quinone + NAD(P)H to a hydroquinone + NAD(P)+. Quinones are cyclic diones derived from aromatic compounds. Membrane bound QOR acts in the respiratory chains of bacteria and mitochondria, while soluble QOR acts to protect from toxic quinones (e.g. DT-diaphorase) or as a soluble eye-lens protein in some vertebrates (e.g. zeta-crystalin). QOR reduces quinones through a semi-quinone intermediate via a NAD(P)H-dependent single electron transfer. QOR is a member of the medium chain dehydrogenase/reductase family, but lacks the zinc-binding sites of the prototypical alcohol dehydrogenases of this group. NAD(P)(H)-dependent oxidoreductases are the major enzymes in the interconversion of alcohols and aldehydes, or ketones. Alcohol dehydrogenase in the liver converts ethanol and NAD+ to acetaldehyde and NADH, while in yeast and some other microorganisms ADH catalyzes the conversion acetaldehyde to ethanol in alcoholic fermentation. ADH is a member of the medium chain alcohol dehydrogenase family (MDR), which has a NAD(P)(H)-binding domain in a Rossmann fold of a beta-alpha form. The NAD(H)-binding region is comprised of 2 structurally similar halves, each of which contacts a mononucleotide. A GxGxxG motif after the first mononucleotide contact half allows the close contact of the coenzyme with the ADH backbone. The N-terminal catalytic domain has a distant homology to GroES. These proteins typically form dimers (typically higher plants, mammals) or tetramers (yeast, bacteria), and have 2 tightly bound zinc atoms per subunit, a catalytic zinc at the active site, and a structural zinc in a lobe of the catalytic domain. NAD(H)-binding occurs in the cleft between the catalytic and coenzyme-binding domains at the active site, and coenzyme binding induces a conformational closing of this cleft. Coenzyme binding typically precedes and contributes to substrate binding. In human ADH catalysis, the zinc ion helps coordinate the alcohol, followed by deprotonation of a histidine, the ribose of NAD, a serine, then the alcohol, which allows the transfer of a hydride to NAD+, creating NADH and a zinc-bound aldehyde or ketone. In yeast and some bacteria, the active site zinc binds an aldehyde, polarizing it, and leading to the reverse reaction.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 461 QPTCPGAQLCTVYYASLNFRDIMLATGK--LSPDA--IPGkwtsqdsllgMEFSGRDAS----------GKRVMGLVPAK 526
Cdd:cd08241  23 EPGAPGEVRIRVEAAGVNFPDLLMIQGKyqVKPPLpfVPG----------SEVAGVVEAvgegvtgfkvGDRVVALTGQG 92

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 527 GLATSVLLSPDFLWDVPSNWTLEEAASVPVVYSTAYYALVVRGRVRPGETLLIHSGSGGVGQAAIAIALSLGCRVFTTVG 606
Cdd:cd08241  93 GFAEEVVVPAAAVFPLPDGLSFEEAAALPVTYGTAYHALVRRARLQPGETVLVLGAAGGVGLAAVQLAKALGARVIAAAS 172

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 607 SAEKRAYLQArfpqLDSTSFANSRDTSFEQHVLWHTGGKGVDLVLNSLAEEKLQASVRCLATHGRFLEIGkF------DL 680
Cdd:cd08241 173 SEEKLALARA----LGADHVIDYRDPDLRERVKALTGGRGVDVVYDPVGGDVFEASLRSLAWGGRLLVIG-FasgeipQI 247

                       250       260       270       280       290       300       310
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 38196957 681 SQNHPLgmaifLKNVTFHGVLLDAFFNESSADWREVWALVQAGIRDGVVRPLKCTVFHGAQVEDAFRYMAQGKA 754
Cdd:cd08241 248 PANLLL-----LKNISVVGVYWGAYARREPELLRANLAELFDLLAEGKIRPHVSAVFPLEQAAEALRALADRKA 316

PIG3 p53-inducible quinone oxidoreductase; PIG3 p53-inducible quinone oxidoreductase, a medium chain dehydrogenase/reductase family member, acts in the apoptotic pathway. PIG3 reduces ortho-quinones, but its apoptotic activity has been attributed to oxidative stress generation, since overexpression of PIG3 accumulates reactive oxygen species. PIG3 resembles the MDR family member quinone reductases, which catalyze the reduction of quinone to hydroxyquinone. NAD(P)(H)-dependent oxidoreductases are the major enzymes in the interconversion of alcohols and aldehydes or ketones. Alcohol dehydrogenase in the liver converts ethanol and NAD+ to acetaldehyde and NADH, while in yeast and some other microorganisms ADH catalyzes the conversion acetaldehyde to ethanol in alcoholic fermentation. ADH is a member of the medium chain alcohol dehydrogenase family (MDR), which has a NAD(P)(H)-binding domain in a Rossmann fold of a beta-alpha form. The NAD(H)-binding region is comprised of 2 structurally similar halves, each of which contacts a mononucleotide. A GxGxxG motif after the first mononucleotide contact half allows the close contact of the coenzyme with the ADH backbone. The N-terminal catalytic domain has a distant homology to GroES. These proteins typically form dimers (typically higher plants, mammals) or tetramers (yeast, bacteria), and have 2 tightly bound zinc atoms per subunit, a catalytic zinc at the active site, and a structural zinc in a lobe of the catalytic domain. NAD(H) binding occurs in the cleft between the catalytic and coenzyme-binding domains at the active site, and coenzyme binding induces a conformational closing of this cleft. Coenzyme binding typically precedes and contributes to substrate binding. In human ADH catalysis, the zinc ion helps coordinate the alcohol, followed by deprotonation of a histidine, the ribose of NAD, a serine, then the alcohol, which allows the transfer of a hydride to NAD+, creating NADH and a zinc-bound aldehyde or ketone. In yeast and some bacteria, the active site zinc binds an aldehyde, polarizing it, and leading to the reverse reaction.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 472 VYYASLNFRDIMLATGKLSPdaiPGKWTSqdsLLGMEFSGRDAS----------GKRVMGLVPAKGLATSVLLSPDFLWD 541
Cdd:cd05276  34 VAAAGVNRADLLQRQGLYPP---PPGASD---ILGLEVAGVVVAvgpgvtgwkvGDRVCALLAGGGYAEYVVVPAGQLLP 107

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 542 VPSNWTLEEAASVPVVYSTAYYALVVRGRVRPGETLLIHSGSGGVGQAAIAIALSLGCRVFTTVGSAEKRAYLQarfpQL 621
Cdd:cd05276 108 VPEGLSLVEAAALPEVFFTAWQNLFQLGGLKAGETVLIHGGASGVGTAAIQLAKALGARVIATAGSEEKLEACR----AL 183

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 622 DSTSFANSRDTSFEQHVLWHTGGKGVDLVLNSLAEEKLQASVRCLATHGRFLEIG-------KFDLsqnhplgMAIFLKN 694
Cdd:cd05276 184 GADVAINYRTEDFAEEVKEATGGRGVDVILDMVGGDYLARNLRALAPDGRLVLIGllggakaELDL-------APLLRKR 256

                       250       260       270       280       290       300       310
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 38196957 695 VTFHG------------VLLDAFfnessadWREVWALvqagIRDGVVRPLKCTVFHGAQVEDAFRYMAQGK 753
Cdd:cd05276 257 LTLTGstlrsrsleekaALAAAF-------REHVWPL----FASGRIRPVIDKVFPLEEAAEAHRRMESNE 316

polyketide synthase; Polyketide synthases produce polyketides in step by step mechanism that is similar to fatty acid synthesis. Enoyl reductase reduces a double to single bond. Erythromycin is one example of a polyketide generated by 3 complex enzymes (megasynthases). 2-enoyl thioester reductase (ETR) catalyzes the NADPH-dependent dependent conversion of trans-2-enoyl acyl carrier protein/coenzyme A (ACP/CoA) to acyl-(ACP/CoA) in fatty acid synthesis. 2-enoyl thioester reductase activity has been linked in Candida tropicalis as essential in maintaining mitiochondrial respiratory function. This ETR family is a part of the medium chain dehydrogenase/reductase family, but lack the zinc coordination sites characteristic of the alcohol dehydrogenases in this family. NAD(P)(H)-dependent oxidoreductases are the major enzymes in the interconversion of alcohols and aldehydes, or ketones. Alcohol dehydrogenase in the liver converts ethanol and NAD+ to acetaldehyde and NADH, while in yeast and some other microorganisms ADH catalyzes the conversion acetaldehyde to ethanol in alcoholic fermentation. ADH is a member of the medium chain alcohol dehydrogenase family (MDR), which have a NAD(P)(H)-binding domain in a Rossmann fold of a beta-alpha form. The NAD(H)-binding region is comprised of 2 structurally similar halves, each of which contacts a mononucleotide. The N-terminal catalytic domain has a distant homology to GroES. These proteins typically form dimers (typically higher plants, mammals) or tetramers (yeast, bacteria), and have 2 tightly bound zinc atoms per subunit, a catalytic zinc at the active site, and a structural zinc in a lobe of the catalytic domain. NAD(H)-binding occurs in the cleft between the catalytic and coenzyme-binding domains at the active site, and coenzyme binding induces a conformational closing of this cleft. Coenzyme binding typically precedes and contributes to substrate binding.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 460 AQPTCPGAQLCTVYYASLNFRDIMLATGkLSPDAIPGKWTSqdsllGMEFSG-RDASGKRVMGLVPAK-----------G 527
Cdd:cd08251   2 VAPPGPGEVRIQVRAFSLNFGDLLCVRG-LYPTMPPYPFTP-----GFEASGvVRAVGPHVTRLAVGDeviagtgesmgG 75

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 528 LATSVLLSPDFLWDVPSNWTLEEAASVPVVYSTAYYALVvRGRVRPGETLLIHSGSGGVGQAAIAIALSLGCRVFTTVGS 607
Cdd:cd08251  76 HATLVTVPEDQVVRKPASLSFEEACALPVVFLTVIDAFA-RAGLAKGEHILIQTATGGTGLMAVQLARLKGAEIYATASS 154

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 608 AEKRAYLQarfpQLDSTSFANSRDTSFEQHVLWHTGGKGVDLVLNSLAEEKLQASVRCLATHGRFLEIGKFDLSQNHPLG 687
Cdd:cd08251 155 DDKLEYLK----QLGVPHVINYVEEDFEEEIMRLTGGRGVDVVINTLSGEAIQKGLNCLAPGGRYVEIAMTALKSAPSVD 230

                       250       260       270       280       290       300
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 38196957 688 MAIFLKNVTFHGVLLDAFFNESSADWREVWALVQAGIRDGVVRPLKCTVFHGAQVEDAFRYMAQGK 753
Cdd:cd08251 231 LSVLSNNQSFHSVDLRKLLLLDPEFIADYQAEMVSLVEEGELRPTVSRIFPFDDIGEAYRYLSDRE 296

Medium chain dehydrogenases/reductase (MDR)/zinc-dependent alcohol dehydrogenase-like family; This group is a member of the medium chain dehydrogenases/reductase (MDR)/zinc-dependent alcohol dehydrogenase-like family, but lacks the zinc-binding sites of the zinc-dependent alcohol dehydrogenases. The medium chain dehydrogenases/reductase (MDR)/zinc-dependent alcohol dehydrogenase-like family, which contains the zinc-dependent alcohol dehydrogenase (ADH-Zn) and related proteins, is a diverse group of proteins related to the first identified member, class I mammalian ADH. MDRs display a broad range of activities and are distinguished from the smaller short chain dehydrogenases (~ 250 amino acids vs. the ~ 350 amino acids of the MDR). The MDR proteins have 2 domains: a C-terminal NAD(P)-binding Rossmann fold domain of a beta-alpha form and an N-terminal catalytic domain with distant homology to GroES. The MDR group contains a host of activities, including the founding alcohol dehydrogenase (ADH), quinone reductase, sorbitol dehydrogenase, formaldehyde dehydrogenase, butanediol DH, ketose reductase, cinnamyl reductase, and numerous others. The zinc-dependent alcohol dehydrogenases (ADHs) catalyze the NAD(P)(H)-dependent interconversion of alcohols to aldehydes or ketones. Active site zinc has a catalytic role, while structural zinc aids in stability. ADH-like proteins typically form dimers (typically higher plants, mammals) or tetramers (yeast, bacteria), and generally have 2 tightly bound zinc atoms per subunit. The active site zinc is coordinated by a histidine, two cysteines, and a water molecule. The second zinc seems to play a structural role, affects subunit interactions, and is typically coordinated by 4 cysteines.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 460 AQPTC-PGAQLCTVYYASLNFRDIMLATGKLS-PDAIPGkwtsqdsLLGMEFSG----------RDASGKRVMGLVPAKG 527
Cdd:cd08272  21 PRPQPgPGQVLVRVHASGVNPLDTKIRRGGAAaRPPLPA-------ILGCDVAGvveavgegvtRFRVGDEVYGCAGGLG 93

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 528 -----LATSVLLSPDFLWDVPSNWTLEEAASVPVVYSTAYYALVVRGRVRPGETLLIHSGSGGVGQAAIAIALSLGCRVF 602
Cdd:cd08272  94 glqgsLAEYAVVDARLLALKPANLSMREAAALPLVGITAWEGLVDRAAVQAGQTVLIHGGAGGVGHVAVQLAKAAGARVY 173

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 603 TTVgSAEKRAYLQarfpQLDSTsFANSRDTSFEQHVLWHTGGKGVDLVLNSLAEEKLQASVRCLATHGRFLEIGkfdLSQ 682
Cdd:cd08272 174 ATA-SSEKAAFAR----SLGAD-PIIYYRETVVEYVAEHTGGRGFDVVFDTVGGETLDASFEAVALYGRVVSIL---GGA 244

                       250       260       270       280       290       300       310
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 38196957 683 NHPLGMAIFlKNVTFHGV--LLDAFFNESSADWREVWALVQAGIRDGVVRP-LKCTVFHGAQVEDAFRYMAQGKA 754
Cdd:cd08272 245 THDLAPLSF-RNATYSGVftLLPLLTGEGRAHHGEILREAARLVERGQLRPlLDPRTFPLEEAAAAHARLESGSA 318

Alcohol dehydrogenases of the MDR family; This group contains proteins related to the zinc-dependent alcohol dehydrogenases. However, while the group has structural zinc site characteristic of these enzymes, it lacks the consensus site for a catalytic zinc. NAD(P)(H)-dependent oxidoreductases are the major enzymes in the interconversion of alcohols and aldehydes, or ketones. Alcohol dehydrogenase in the liver converts ethanol and NAD+ to acetaldehyde and NADH, while in yeast and some other microorganisms ADH catalyzes the conversion acetaldehyde to ethanol in alcoholic fermentation. ADH is a member of the medium chain alcohol dehydrogenase family (MDR), which has a NAD(P)(H)-binding domain in a Rossmann fold of a beta-alpha form. The NAD(H)-binding region is comprised of 2 structurally similar halves, each of which contacts a mononucleotide. A GxGxxG motif after the first mononucleotide contact half allows the close contact of the coenzyme with the ADH backbone. The N-terminal catalytic domain has a distant homology to GroES. These proteins typically form dimers (typically higher plants, mammals) or tetramers (yeast, bacteria), and have 2 tightly bound zinc atoms per subunit, a catalytic zinc at the active site, and a structural zinc in a lobe of the catalytic domain. NAD(H)-binding occurs in the cleft between the catalytic and coenzyme-binding domains at the active site, and coenzyme binding induces a conformational closing of this cleft. Coenzyme binding typically precedes and contributes to substrate binding. In human ADH catalysis, the zinc ion helps coordinate the alcohol, followed by deprotonation of a histidine, the ribose of NAD, a serine, then the alcohol, which allows the transfer of a hydride to NAD+, creating NADH and a zinc-bound aldehyde or ketone. In yeast and some bacteria, the active site zinc binds an aldehyde, polarizing it, and leading to the reverse reaction.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 510 SGRDA--SGKRVMGLVPAKGLATSVLLSPDFLWDVPSNWTLEEAASVPVVYSTAYYALVVRGRVRPGETLLIHSGSGGVG 587
Cdd:cd08266 101 AGRENlcAQYGILGEHVDGGYAEYVAVPARNLLPIPDNLSFEEAAAAPLTFLTAWHMLVTRARLRPGETVLVHGAGSGVG 180

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 588 QAAIAIALSLGCRVFTTVGSAEKRAYLQArfpqLDSTSFANSRDTSFEQHVLWHTGGKGVDLVLNSLAEEKLQASVRCLA 667
Cdd:cd08266 181 SAAIQIAKLFGATVIATAGSEDKLERAKE----LGADYVIDYRKEDFVREVRELTGKRGVDVVVEHVGAATWEKSLKSLA 256

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 668 THGRFLEIG-------KFDLsqnhplgMAIFLKNVTFHGVlldafFNESSADWREVWALVQAgirdGVVRPLKCTVFHGA 740
Cdd:cd08266 257 RGGRLVTCGattgyeaPIDL-------RHVFWRQLSILGS-----TMGTKAELDEALRLVFR----GKLKPVIDSVFPLE 320

                       250
                ....*....|...
gi 38196957 741 QVEDAFRYMAQGK 753
Cdd:cd08266 321 EAAEAHRRLESRE 333

alcohol dehydrogenase and quinone reductase-like medium chain degydrogenases/reductases; Members identified as zinc-dependent alcohol dehydrogenases and quinone oxidoreductase. QOR catalyzes the conversion of a quinone + NAD(P)H to a hydroquinone + NAD(P)+. Quinones are cyclic diones derived from aromatic compounds. Membrane bound QOR actin the respiratory chains of bacteria and mitochondria, while soluble QOR acts to protect from toxic quinones (e.g. DT-diaphorase) or as a soluble eye-lens protein in some vertebrates (e.g. zeta-crystalin). QOR reduces quinones through a semi-quinone intermediate via a NAD(P)H-dependent single electron transfer. QOR is a member of the medium chain dehydrogenase/reductase family, but lacks the zinc-binding sites of the prototypical alcohol dehydrogenases of this group. NAD(P)(H)-dependent oxidoreductases are the major enzymes in the interconversion of alcohols and aldehydes, or ketones. Alcohol dehydrogenase in the liver converts ethanol and NAD+ to acetaldehyde and NADH, while in yeast and some other microorganisms ADH catalyzes the conversion acetaldehyde to ethanol in alcoholic fermentation. ADH is a member of the medium chain alcohol dehydrogenase family (MDR), which has a NAD(P)(H)-binding domain in a Rossmann fold of a beta-alpha form. The NAD(H)-binding region is comprised of 2 structurally similar halves, each of which contacts a mononucleotide. A GxGxxG motif after the first mononucleotide contact half allows the close contact of the coenzyme with the ADH backbone. The N-terminal catalytic domain has a distant homology to GroES. These proteins typically form dimers (typically higher plants, mammals) or tetramers (yeast, bacteria), and have 2 tightly bound zinc atoms per subunit, a catalytic zinc at the active site and a structural zinc in a lobe of the catalytic domain. NAD(H) binding occurs in the cleft between the catalytic and coenzyme-binding domains at the active site, and coenzyme binding induces a conformational closing of this cleft. Coenzyme binding typically precedes and contributes to substrate binding. In human ADH catalysis, the zinc ion helps coordinate the alcohol, followed by deprotonation of a histidine, the ribose of NAD, a serine, then the alcohol, which allows the transfer of a hydride to NAD+, creating NADH and a zinc-bound aldehyde or ketone. In yeast and some bacteria, the active site zinc binds an aldehyde, polarizing it, and leading to the reverse reaction.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 472 VYYASLNFRDIMLATGKLS---PDAIPgkwtsqdSLLGMEFSGR-DASGK---------RVMGLVPAK---GLATSVLLS 535
Cdd:cd05289  34 VHAAGVNPVDLKIREGLLKaafPLTLP-------LIPGHDVAGVvVAVGPgvtgfkvgdEVFGMTPFTrggAYAEYVVVP 106

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 536 PDFLWDVPSNWTLEEAASVPVVYSTAYYALVVRGRVRPGETLLIHSGSGGVGQAAIAIALSLGCRVFTTVgSAEKRAYLQ 615
Cdd:cd05289 107 ADELALKPANLSFEEAAALPLAGLTAWQALFELGGLKAGQTVLIHGAAGGVGSFAVQLAKARGARVIATA-SAANADFLR 185

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 616 ArfpqLDSTSFANSRDTSFEQHVLWHtggkGVDLVLNSLAEEKLQASVRCLATHGRFLEIgkfdlsqnhpLGMAIFLKNV 695
Cdd:cd05289 186 S----LGADEVIDYTKGDFERAAAPG----GVDAVLDTVGGETLARSLALVKPGGRLVSI----------AGPPPAEQAA 247

                       250       260       270       280       290       300
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 38196957 696 TFHGVLLDAFF-NESSADWREVWALVqagiRDGVVRPLKCTVFHGAQVEDAFRYMAQGKA 754
Cdd:cd05289 248 KRRGVRAGFVFvEPDGEQLAELAELV----EAGKLRPVVDRVFPLEDAAEAHERLESGHA 303