phenylcoumaran benzylic ether reductase (PCBER) like, atypical (a) SDRs; PCBER and pinoresinol-lariciresinol reductases are NADPH-dependent aromatic alcohol reductases, and are atypical members of the SDR family. Other proteins in this subgroup are identified as eugenol synthase. These proteins contain an N-terminus characteristic of NAD(P)-binding proteins and a small C-terminal domain presumed to be involved in substrate binding, but they do not have the conserved active site Tyr residue typically found in SDRs. Numerous other members have unknown functions. The glycine rich NADP-binding motif in this subgroup is of 2 forms: GXGXXG and G[GA]XGXXG; it tends to be atypical compared with the forms generally seen in classical or extended SDRs. The usual SDR active site tetrad is not present, but a critical active site Lys at the usual SDR position has been identified in various members, though other charged and polar residues are found at this position in this subgroup. Atypical SDR-related proteins retain the Rossmann fold of the SDRs, but have limited sequence identity and generally lack the catalytic properties of the archetypical members. Atypical SDRs include biliverdin IX beta reductase (BVR-B,aka flavin reductase), NMRa (a negative transcriptional regulator of various fungi), progesterone 5-beta-reductase like proteins, phenylcoumaran benzylic ether and pinoresinol-lariciresinol reductases, phenylpropene synthases, eugenol synthase, triphenylmethane reductase, isoflavone reductases, and others. SDRs are a functionally diverse family of oxidoreductases that have a single domain with a structurally conserved Rossmann fold, an NAD(P)(H)-binding region, and a structurally diverse C-terminal region. Sequence identity between different SDR enzymes is typically in the 15-30% range; they 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 15-hydroxyprostaglandin dehydrogenase numbering). In addition to the Tyr and Lys, there is often an upstream Ser and/or an Asn, 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. In addition to the Rossmann fold core region typical of all SDRs, extended SDRs have a less conserved C-terminal extension of approximately 100 amino acids, 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 ketoacyl reductases have a TGXXXGX(1-2)G NAD(P)-binding motif.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371   7 KILVIGGTGHIGKLIIEASVKA-GHSTLALVREASLSDPNkgktvqnFKDFGVTLLHGDLNDHESLVKAIKQADVVISTV 85
Cdd:cd05259    1 KIAIAGATGTLGGPIVSALLASpGFTVTVLTRPSSTSSNE-------FQPSGVKVVPVDYASHESLVAALKGVDAVISAL 73

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371  86 GSMQILDQTKIISAIKEAGnVKRFLPSEFGMDVDKSSAVEPAkSAFGRKLQTRRDIEA--EGIPYTYLVTNYFAGYYLPT 163
Cdd:cd05259   74 GGAAIGDQLKLIDAAIAAG-VKRFIPSEFGVDYDRIGALPLL-DLFDEKRDVRRYLRAknAGLPWTYVSTGMFLDYLLEP 151

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371 164 LvqlePGLTSPPRDKVKIFGDGNVKAVINKEEDIAAYTIKAVD-DPRTLNKTLYINPpnNTLSMNEIVTLWEKKIGKSVE 242
Cdd:cd05259  152 L----FGVVDLANRTATIYGDGETKFAFTTLEDIGRAVARALThPDRTLNRVVFVAG--DVVTQNELIALVERVTGRKFE 225

                        250       260       270       280       290       300
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 240254371 243 KIYMSEEQIFKSIQESPV--PFNVLLSINHAVFVKGDqtnftiepsfGFEASEL-YPDIKYTSIDEY 306
Cdd:cd05259  226 RTYVSEEELLEELIEAAPagLLNYVIAFLHGLGIGGG----------DVEKSDAeYLGLKVETVEEL 282

3,8-divinyl protochlorophyllide a 8-vinyl reductase

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371   2 ASEKSKILVIGGTGHIGKLIIEASVKAGHSTLALVREASLSDPNKGKTvQNFKDF-GVTLLHGDLNDHESLVKAIKQ--- 77
Cdd:PLN02657  57 EPKDVTVLVVGATGYIGKFVVRELVRRGYNVVAVAREKSGIRGKNGKE-DTKKELpGAEVVFGDVTDADSLRKVLFSegd 135

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371  78 -ADVVISTVGSMQ--ILDQTKI-ISAIKEAGNVKRflpsEFGmdvdkssavepAK-----SA---------FGR-KLQTR 138
Cdd:PLN02657 136 pVDVVVSCLASRTggVKDSWKIdYQATKNSLDAGR----EVG-----------AKhfvllSAicvqkplleFQRaKLKFE 200

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371 139 RDIEAEGIPYTYLV---TNYF---AGyylptlvQLEpgltspprdKVK------IFGDGNVKAV--INkEEDIAAYTIKA 204
Cdd:PLN02657 201 AELQALDSDFTYSIvrpTAFFkslGG-------QVE---------IVKdggpyvMFGDGKLCACkpIS-EADLASFIADC 263

                        250       260       270
                 ....*....|....*....|....*....|....*.
gi 240254371 205 VDDPRTLNKTLYINPPNNTLSMNEIVTLWEKKIGKS 240
Cdd:PLN02657 264 VLDESKINKVLPIGGPGKALTPLEQGEMLFRILGKE 299

phenylcoumaran benzylic ether reductase (PCBER) like, atypical (a) SDRs; PCBER and pinoresinol-lariciresinol reductases are NADPH-dependent aromatic alcohol reductases, and are atypical members of the SDR family. Other proteins in this subgroup are identified as eugenol synthase. These proteins contain an N-terminus characteristic of NAD(P)-binding proteins and a small C-terminal domain presumed to be involved in substrate binding, but they do not have the conserved active site Tyr residue typically found in SDRs. Numerous other members have unknown functions. The glycine rich NADP-binding motif in this subgroup is of 2 forms: GXGXXG and G[GA]XGXXG; it tends to be atypical compared with the forms generally seen in classical or extended SDRs. The usual SDR active site tetrad is not present, but a critical active site Lys at the usual SDR position has been identified in various members, though other charged and polar residues are found at this position in this subgroup. Atypical SDR-related proteins retain the Rossmann fold of the SDRs, but have limited sequence identity and generally lack the catalytic properties of the archetypical members. Atypical SDRs include biliverdin IX beta reductase (BVR-B,aka flavin reductase), NMRa (a negative transcriptional regulator of various fungi), progesterone 5-beta-reductase like proteins, phenylcoumaran benzylic ether and pinoresinol-lariciresinol reductases, phenylpropene synthases, eugenol synthase, triphenylmethane reductase, isoflavone reductases, and others. SDRs are a functionally diverse family of oxidoreductases that have a single domain with a structurally conserved Rossmann fold, an NAD(P)(H)-binding region, and a structurally diverse C-terminal region. Sequence identity between different SDR enzymes is typically in the 15-30% range; they 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 15-hydroxyprostaglandin dehydrogenase numbering). In addition to the Tyr and Lys, there is often an upstream Ser and/or an Asn, 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. In addition to the Rossmann fold core region typical of all SDRs, extended SDRs have a less conserved C-terminal extension of approximately 100 amino acids, 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 ketoacyl reductases have a TGXXXGX(1-2)G NAD(P)-binding motif.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371   7 KILVIGGTGHIGKLIIEASVKA-GHSTLALVREASLSDPNkgktvqnFKDFGVTLLHGDLNDHESLVKAIKQADVVISTV 85
Cdd:cd05259    1 KIAIAGATGTLGGPIVSALLASpGFTVTVLTRPSSTSSNE-------FQPSGVKVVPVDYASHESLVAALKGVDAVISAL 73

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371  86 GSMQILDQTKIISAIKEAGnVKRFLPSEFGMDVDKSSAVEPAkSAFGRKLQTRRDIEA--EGIPYTYLVTNYFAGYYLPT 163
Cdd:cd05259   74 GGAAIGDQLKLIDAAIAAG-VKRFIPSEFGVDYDRIGALPLL-DLFDEKRDVRRYLRAknAGLPWTYVSTGMFLDYLLEP 151

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371 164 LvqlePGLTSPPRDKVKIFGDGNVKAVINKEEDIAAYTIKAVD-DPRTLNKTLYINPpnNTLSMNEIVTLWEKKIGKSVE 242
Cdd:cd05259  152 L----FGVVDLANRTATIYGDGETKFAFTTLEDIGRAVARALThPDRTLNRVVFVAG--DVVTQNELIALVERVTGRKFE 225

                        250       260       270       280       290       300
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 240254371 243 KIYMSEEQIFKSIQESPV--PFNVLLSINHAVFVKGDqtnftiepsfGFEASEL-YPDIKYTSIDEY 306
Cdd:cd05259  226 RTYVSEEELLEELIEAAPagLLNYVIAFLHGLGIGGG----------DVEKSDAeYLGLKVETVEEL 282

triphenylmethane reductase (TMR)-like proteins, NMRa-like, atypical (a) SDRs; TMR is an atypical NADP-binding protein of the SDR family. It lacks the active site residues of the SDRs but has a glycine rich NAD(P)-binding motif that matches the extended SDRs. Proteins in this subgroup however, are more similar in length to the classical SDRs. TMR was identified as a reducer of triphenylmethane dyes, important environmental pollutants. This subgroup also includes Escherichia coli NADPH-dependent quinine oxidoreductase (QOR2), which catalyzes two-electron reduction of quinone; but is unlikely to play a major role in protecting against quinone cytotoxicity. Atypical SDRs are distinct from classical SDRs. Atypical SDRs include biliverdin IX beta reductase (BVR-B,aka flavin reductase), NMRa (a negative transcriptional regulator of various fungi), progesterone 5-beta-reductase like proteins, phenylcoumaran benzylic ether and pinoresinol-lariciresinol reductases, phenylpropene synthases, eugenol synthase, triphenylmethane reductase, isoflavone reductases, and others. SDRs are a functionally diverse family of oxidoreductases that have a single domain with a structurally conserved Rossmann fold, an NAD(P)(H)-binding region, and a structurally diverse C-terminal region. Sequence identity between different SDR enzymes is typically in the 15-30% range; they 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 15-hydroxyprostaglandin dehydrogenase numbering). In addition to the Tyr and Lys, there is often an upstream Ser and/or an Asn, 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. In addition to the Rossmann fold core region typical of all SDRs, extended SDRs have a less conserved C-terminal extension of approximately 100 amino acids, 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 ketoacyl reductases have a TGXXXGX(1-2)G NAD(P)-binding motif.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371   8 ILVIGGTGHIGKLIIEASVKAGHSTLALVReaslsDPNKGKTvqnFKDFGVTLLHGDLNDHESLVKAIKQADVV--ISTV 85
Cdd:cd05269    1 ILVTGATGKLGTAVVELLLAKVASVVALVR-----NPEKAKA---FAADGVEVRQGDYDDPETLERAFEGVDRLllISPS 72

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371  86 GSMQILDQTK-IISAIKEAGnVKRFLPSEFgmdvdkSSAVEPAKSAFGRK-LQTRRDIEAEGIPYTYLVTNYFAgyylpt 163
Cdd:cd05269   73 DLEDRIQQHKnFIDAAKQAG-VKHIVYLSA------SGADEDSPFLLARDhGATEKYLEASGIPYTILRPGWFM------ 139

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371 164 lvQLEPGLTSPPRDKVKIF---GDGNVKAVinKEEDIAAYTIKAVDDPRTLNKTLYINPPnNTLSMNEIVTLWEKKIGKS 240
Cdd:cd05269  140 --DNLLEFLPSILEEGTIYgpaGDGKVAFV--DRRDIAEAAAAALTEPGHEGKVYNLTGP-EALSYAELAAILSEALGKP 214

                        250       260       270       280
                 ....*....|....*....|....*....|....*....|....*
gi 240254371 241 VEKIYMSEEQIFKSIQESPVP---FNVLLSInHAVFVKGDQTNFT 282
Cdd:cd05269  215 VRYVPVSPDEAARELLAAGLPegfAALLASL-YAAIRKGELAVVS 258

Putative NADH-flavin reductase [General function prediction only];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371   7 KILVIGGTGHIGKLIIEASVKAGHSTLALVReaslsDPNKGKTVQNfkdfGVTLLHGDLNDHESLVKAIKQADVVISTVG 86
Cdd:COG2910    1 KIAVIGATGRVGSLIVREALARGHEVTALVR-----NPEKLPDEHP----GLTVVVGDVLDPAAVAEALAGADAVVSALG 71

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371  87 S------MQILDQTK-IISAIKEAGnVKRF--------LPSEFGMDVDKSSAVEPAKSAFGRKLQTRRDIEAEGIPYTYL 151
Cdd:COG2910   72 AgggnptTVLSDGARaLIDAMKAAG-VKRLivvggagsLDVAPGLGLDTPGFPAALKPAAAAKAAAEELLRASDLDWTIV 150

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 240254371 152 vtnyfagyyLPTlvQLEPGltsPPRDKVKIFGDGNVK--AVINKeEDIAAYTIKAVDDPRTLNKTLYI 217
Cdd:COG2910  151 ---------RPA--ALTDG---ERTGRYRLGGDGLLVdaSSISR-ADVAVALLDELEDPAHIRQRFTV 203

atypical (a) SDRs, subgroup 5; This subgroup contains atypical SDRs, some of which are identified as putative NAD(P)-dependent epimerases, one as a putative NAD-dependent epimerase/dehydratase. Atypical SDRs are distinct from classical SDRs. Members of this subgroup have a glycine-rich NAD(P)-binding motif that is very similar to the extended SDRs, GXXGXXG, and binds NADP. Generally, this subgroup has poor conservation of the active site tetrad; however, individual sequences do contain matches to the YXXXK active site motif, the upstream Ser, and there is a highly conserved Asp in place of the usual active site Asn throughout the subgroup. Atypical SDRs generally lack the catalytic residues characteristic of the SDRs, and their glycine-rich NAD(P)-binding motif is often different from the forms normally seen in classical or extended SDRs. Atypical SDRs include biliverdin IX beta reductase (BVR-B,aka flavin reductase), NMRa (a negative transcriptional regulator of various fungi), progesterone 5-beta-reductase like proteins, phenylcoumaran benzylic ether and pinoresinol-lariciresinol reductases, phenylpropene synthases, eugenol synthase, triphenylmethane reductase, isoflavone reductases, and others. SDRs are a functionally diverse family of oxidoreductases that have a single domain with a structurally conserved Rossmann fold, an NAD(P)(H)-binding region, and a structurally diverse C-terminal region. Sequence identity between different SDR enzymes is typically in the 15-30% range; they 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 15-hydroxyprostaglandin dehydrogenase numbering). In addition to the Tyr and Lys, there is often an upstream Ser and/or an Asn, 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. In addition to the Rossmann fold core region typical of all SDRs, extended SDRs have a less conserved C-terminal extension of approximately 100 amino acids, 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 ketoacyl reductases have a TGXXXGX(1-2)G NAD(P)-binding motif.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371   7 KILVIGGTGHIGKLIIEASVKAGHSTLALVREASlsdpnkgkTVQNFKDFGVTLLHGDLNDHESLVKAIKQADVVISTVG 86
Cdd:cd05243    1 KVLVVGATGKVGRHVVRELLDRGYQVRALVRDPS--------QAEKLEAAGAEVVVGDLTDAESLAAALEGIDAVISAAG 72

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371  87 S-MQILDQT---------KIISAIKEAGnVKRF-LPSEFGmdVDKSS-------AVEPAKSAFGRKLQtrrdieAEGIPY 148
Cdd:cd05243   73 SgGKGGPRTeavdydgniNLIDAAKKAG-VKRFvLVSSIG--ADKPShplealgPYLDAKRKAEDYLR------ASGLDY 143

                        170       180       190       200       210       220       230
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371 149 tylvtnyfagyylpTLVQLePGLTSPPRD--KVKIFGDG-NVKAVINkEEDIAAYTIKAVDDPRTLNKTL 215
Cdd:cd05243  144 --------------TIVRP-GGLTDDPAGtgRVVLGGDGtRLDGPIS-RADVAEVLAEALDTPAAIGKTF 197

NmrA (a transcriptional regulator) and HSCARG (an NADPH sensor) like proteins, atypical (a) SDRs; NmrA and HSCARG like proteins. NmrA is a negative transcriptional regulator of various fungi, involved in the post-translational modulation of the GATA-type transcription factor AreA. NmrA lacks the canonical GXXGXXG NAD-binding motif and has altered residues at the catalytic triad, including a Met instead of the critical Tyr residue. NmrA may bind nucleotides but appears to lack any dehydrogenase activity. HSCARG has been identified as a putative NADP-sensing molecule, and redistributes and restructures in response to NADPH/NADP ratios. Like NmrA, it lacks most of the active site residues of the SDR family, but has an NAD(P)-binding motif similar to the extended SDR family, GXXGXXG. SDRs are a functionally diverse family of oxidoreductases that have a single domain with a structurally conserved Rossmann fold, an NAD(P)(H)-binding region, and a structurally diverse C-terminal region. Sequence identity between different SDR enzymes is typically in the 15-30% range; they catalyze a wide range of activities including the metabolism of steroids, cofactors, carbohydrates, lipids, aromatic compounds, and amino acids, and act in redox sensing. Atypical SDRs are distinct from classical SDRs. 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 15-hydroxyprostaglandin dehydrogenase numbering). In addition to the Tyr and Lys, there is often an upstream Ser and/or an Asn, 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. In addition to the Rossmann fold core region typical of all SDRs, extended SDRs have a less conserved C-terminal extension of approximately 100 amino acids, 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 ketoacyl reductases have a TGXXXGX(1-2)G NAD(P)-binding motif.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371   8 ILVIGGTGHIGKLIIEASVK-AGHSTLALVReaslsDPNKgKTVQNFKDFGVTLLHGDLNDHESLVKAIKQADVVIS--- 83
Cdd:cd05251    1 ILVFGATGKQGGSVVRALLKdPGFKVRALTR-----DPSS-PAAKALAAPGVEVVQGDLDDPESLEAALKGVYGVFLvtd 74

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371  84 --TVGSMQILDQ-TKIISAIKEAGnVKRFLPSEFGmDVDKSSavePAKSAFGRKLQTRRDIEAEGIPYTYL-VTNY---F 156
Cdd:cd05251   75 fwEAGGEDEIAQgKNVVDAAKRAG-VQHFVFSSVP-DVEKLT---LAVPHFDSKAEVEEYIRASGLPATILrPAFFmenF 149

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371 157 AGYYLPTLvqLEPGLTSPPrdkvkIFGDGNVKAVINKEEDIAAYTIKAVDDP-RTLNKTLYINPPNntLSMNEIVTLWEK 235
Cdd:cd05251  150 LTPPAPQK--MEDGTLTLV-----LPLDPDTKLPMIDVADIGPAVAAIFKDPaKFNGKTIELAGDE--LTPEEIAAAFSK 220

                        250
                 ....*....|....*...
gi 240254371 236 KIGKSVEkiYMSEEQIFK 253
Cdd:cd05251  221 VLGKPVT--YVQVEEWLR 236

atypical (a) SDRs, subgroup 1; Atypical SDRs in this subgroup are poorly defined and have been identified putatively as isoflavones reductase, sugar dehydratase, mRNA binding protein etc. Atypical SDRs are distinct from classical SDRs. Members of this subgroup retain the canonical active site triad (though not the upstream Asn found in most SDRs) but have an unusual putative glycine-rich NAD(P)-binding motif, GGXXXXG, in the usual location. Atypical SDRs generally lack the catalytic residues characteristic of the SDRs, and their glycine-rich NAD(P)-binding motif is often different from the forms normally seen in classical or extended SDRs. Atypical SDRs include biliverdin IX beta reductase (BVR-B,aka flavin reductase), NMRa (a negative transcriptional regulator of various fungi), progesterone 5-beta-reductase like proteins, phenylcoumaran benzylic ether and pinoresinol-lariciresinol reductases, phenylpropene synthases, eugenol synthase, triphenylmethane reductase, isoflavone reductases, and others. SDRs are a functionally diverse family of oxidoreductases that have a single domain with a structurally conserved Rossmann fold, an NAD(P)(H)-binding region, and a structurally diverse C-terminal region. Sequence identity between different SDR enzymes is typically in the 15-30% range; they 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 15-hydroxyprostaglandin dehydrogenase numbering). In addition to the Tyr and Lys, there is often an upstream Ser and/or an Asn, 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. In addition to the Rossmann fold core region typical of all SDRs, extended SDRs have a less conserved C-terminal extension of approximately 100 amino acids, 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 ketoacyl reductases have a TGXXXGX(1-2)G NAD(P)-binding motif.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371   7 KILVIGGTGHIGKLIIEASVKAGHS-TLAlvreaslsdpNKGKTvQNFKDFGVTLLHGDLNDHESLVKAIK--QADVVIS 83
Cdd:cd05265    2 KILIIGGTRFIGKALVEELLAAGHDvTVF----------NRGRT-KPDLPEGVEHIVGDRNDRDALEELLGgeDFDVVVD 70

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371  84 TVG--SMQILDQTKI----------ISAI----KEAGNVKRFLPSEFGMDVDKSsavEPAKSAFGRKLQTRRDIEAEGIP 147
Cdd:cd05265   71 TIAytPRQVERALDAfkgrvkqyifISSAsvylKPGRVITESTPLREPDAVGLS---DPWDYGRGKRAAEDVLIEAAAFP 147

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371 148 YTYLVTNYFAGYYLPT------LVQLEPGltspprDKVKIFGDGNVKAVINKEEDIAAYTIKAVDDPRTLNKTLYINPPn 221
Cdd:cd05265  148 YTIVRPPYIYGPGDYTgrlayfFDRLARG------RPILVPGDGHSLVQFIHVKDLARALLGAAGNPKAIGGIFNITGD- 220

                        250       260       270
                 ....*....|....*....|....*....|
gi 240254371 222 NTLSMNEIVTLWEKKIGKSVEKIYMSEEQI 251
Cdd:cd05265  221 EAVTWDELLEACAKALGKEAEIVHVEEDFL 250

atypical (a) SDRs, subgroup 7; This subgroup contains atypical SDRs of unknown function. Members of this subgroup have a glycine-rich NAD(P)-binding motif consensus that matches the extended SDRs, TGXXGXXG, but lacks the characteristic active site residues of the SDRs. This subgroup has basic residues (HXXXR) in place of the active site motif YXXXK, these may have a catalytic role. Atypical SDRs generally lack the catalytic residues characteristic of the SDRs, and their glycine-rich NAD(P)-binding motif is often different from the forms normally seen in classical or extended SDRs. Atypical SDRs include biliverdin IX beta reductase (BVR-B,aka flavin reductase), NMRa (a negative transcriptional regulator of various fungi), progesterone 5-beta-reductase like proteins, phenylcoumaran benzylic ether and pinoresinol-lariciresinol reductases, phenylpropene synthases, eugenol synthase, triphenylmethane reductase, isoflavone reductases, and others. SDRs are a functionally diverse family of oxidoreductases that have a single domain with a structurally conserved Rossmann fold, an NAD(P)(H)-binding region, and a structurally diverse C-terminal region. Sequence identity between different SDR enzymes is typically in the 15-30% range; they 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 15-hydroxyprostaglandin dehydrogenase numbering). In addition to the Tyr and Lys, there is often an upstream Ser and/or an Asn, 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. In addition to the Rossmann fold core region typical of all SDRs, extended SDRs have a less conserved C-terminal extension of approximately 100 amino acids, 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 ketoacyl reductases have a TGXXXGX(1-2)G NAD(P)-binding motif.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371   7 KILVIGGTGHIGKLIIEASVKAGHSTLALVReaslSDPNKGKtvqnFKDFGVTLLHGDLNDHESLVKAIKQADVVIST-- 84
Cdd:cd05262    2 KVFVTGATGFIGSAVVRELVAAGHEVVGLAR----SDAGAAK----LEAAGAQVHRGDLEDLDILRKAAAEADAVIHLaf 73

                         90       100       110
                 ....*....|....*....|....*....|...
gi 240254371  85 VGSMQILDQ-----TKIISAIKEA--GNVKRFL 110
Cdd:cd05262   74 THDFDNFAQacevdRRAIEALGEAlrGTGKPLI 106

NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, subunit 9, 39 kDa, (NDUFA9) -like, atypical (a) SDRs; This subgroup of extended SDR-like proteins are atypical SDRs. They have a glycine-rich NAD(P)-binding motif similar to the typical SDRs, GXXGXXG, and have the YXXXK active site motif (though not the other residues of the SDR tetrad). Members identified include NDUFA9 (mitochondrial) and putative nucleoside-diphosphate-sugar epimerase. Atypical SDRs generally lack the catalytic residues characteristic of the SDRs, and their glycine-rich NAD(P)-binding motif is often different from the forms normally seen in classical or extended SDRs. Atypical SDRs include biliverdin IX beta reductase (BVR-B,aka flavin reductase), NMRa (a negative transcriptional regulator of various fungi), progesterone 5-beta-reductase like proteins, phenylcoumaran benzylic ether and pinoresinol-lariciresinol reductases, phenylpropene synthases, eugenol synthase, triphenylmethane reductase, isoflavone reductases, and others. SDRs are a functionally diverse family of oxidoreductases that have a single domain with a structurally conserved Rossmann fold, an NAD(P)(H)-binding region, and a structurally diverse C-terminal region. Sequence identity between different SDR enzymes is typically in the 15-30% range; they 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 15-hydroxyprostaglandin dehydrogenase numbering). In addition to the Tyr and Lys, there is often an upstream Ser and/or an Asn, 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. In addition to the Rossmann fold core region typical of all SDRs, extended SDRs have a less conserved C-terminal extension of approximately 100 amino acids, 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 ketoacyl reductases have a TGXXXGX(1-2)G NAD(P)-binding motif.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371   7 KILVIGGTGHIGKLIIEASVKAGHSTLALVReaslSDPNKGKtVQNFKDFG-VTLLHGDLNDHESLVKAIKQADVVISTV 85
Cdd:cd05271    2 VVTVFGATGFIGRYVVNRLAKRGSQVIVPYR----CEAYARR-LLVMGDLGqVLFVEFDLRDDESIRKALEGSDVVINLV 76

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371  86 GSMQildQTK--------------IISAIKEAGnVKRFLP-SEFGMDVDkssavepAKSAFgrkLQTRRDIEAEgipyty 150
Cdd:cd05271   77 GRLY---ETKnfsfedvhvegperLAKAAKEAG-VERLIHiSALGADAN-------SPSKY---LRSKAEGEEA------ 136

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371 151 lVTNYFagyylPTLVQLEPGLtspprdkvkIFGDGN--------------VKAVINKEE---------DIAAYTIKAVDD 207
Cdd:cd05271  137 -VREAF-----PEATIVRPSV---------VFGREDrflnrfakllaflpFPPLIGGGQtkfqpvyvgDVAEAIARALKD 201

                        250       260       270
                 ....*....|....*....|....*....|....*....
gi 240254371 208 PRTLNKTLYINPPnNTLSMNEIVTLWEKKIGKSVEKIYM 246
Cdd:cd05271  202 PETEGKTYELVGP-KVYTLAELVELLRRLGGRKRRVLPL 239

atypical (a) SDRs, subgroup 6; These atypical SDR family members of unknown function have only a partial match to a prototypical glycine-rich NAD(P)-binding motif consensus, GXXG, which conserves part of the motif of extended SDR. Furthermore, they lack the characteristic active site residues of the SDRs. This subgroup is related to phenylcoumaran benzylic ether reductase, an NADPH-dependent aromatic alcohol reductase. One member is identified as a putative NAD-dependent epimerase/dehydratase. Atypical SDRs generally lack the catalytic residues characteristic of the SDRs, and their glycine-rich NAD(P)-binding motif is often different from the forms normally seen in classical or extended SDRs. Atypical SDRs include biliverdin IX beta reductase (BVR-B,aka flavin reductase), NMRa (a negative transcriptional regulator of various fungi), progesterone 5-beta-reductase like proteins, phenylcoumaran benzylic ether and pinoresinol-lariciresinol reductases, phenylpropene synthases, eugenol synthase, triphenylmethane reductase, isoflavone reductases, and others. SDRs are a functionally diverse family of oxidoreductases that have a single domain with a structurally conserved Rossmann fold, an NAD(P)(H)-binding region, and a structurally diverse C-terminal region. Sequence identity between different SDR enzymes is typically in the 15-30% range; they 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 15-hydroxyprostaglandin dehydrogenase numbering). In addition to the Tyr and Lys, there is often an upstream Ser and/or an Asn, 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. In addition to the Rossmann fold core region typical of all SDRs, extended SDRs have a less conserved C-terminal extension of approximately 100 amino acids, 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 ketoacyl reductases have a TGXXXGX(1-2)G NAD(P)-binding motif.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371   7 KILVIGGTGHIGKLIIEASVKAGHSTLAL-VREAslsdpnkgKTVQNFKDFGVTLLHGDLNDHESLVKAIKQADVVISTV 85
Cdd:cd05267    2 KVLILGANGEIAREATTMLLENSNVELTLfLRNA--------HRLLHLKSARVTVVEGDALNSDDLKAAMRGQDVVYANL 73

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371  86 GSMQILDQTKIISAIKEAGNVKRF-----------LPSEFGmdvdkssavEPAKSAFGRKLQTRRD----IEAEGIPYTY 150
Cdd:cd05267   74 GGTDLDQQAENVVQAMKAVGVKRLiwttslgiydeVPGKFG---------EWNKEFIGNYLAPYRKsaavIENSDLDYTL 144

                 .
gi 240254371 151 L 151
Cdd:cd05267  145 L 145

atypical (a) SDRs, subgroup 2; This subgroup contains atypical SDRs, one member is identified as Escherichia coli protein ybjT, function unknown. Atypical SDRs are distinct from classical SDRs. Members of this subgroup have a glycine-rich NAD(P)-binding motif consensus that generally matches the extended SDRs, TGXXGXXG, but lacks the characteristic active site residues of the SDRs. This subgroup has basic residues (HXXXR) in place of the active site motif YXXXK, these may have a catalytic role. Atypical SDRs generally lack the catalytic residues characteristic of the SDRs, and their glycine-rich NAD(P)-binding motif is often different from the forms normally seen in classical or extended SDRs. Atypical SDRs include biliverdin IX beta reductase (BVR-B,aka flavin reductase), NMRa (a negative transcriptional regulator of various fungi), progesterone 5-beta-reductase like proteins, phenylcoumaran benzylic ether and pinoresinol-lariciresinol reductases, phenylpropene synthases, eugenol synthase, triphenylmethane reductase, isoflavone reductases, and others. SDRs are a functionally diverse family of oxidoreductases that have a single domain with a structurally conserved Rossmann fold, an NAD(P)(H)-binding region, and a structurally diverse C-terminal region. Sequence identity between different SDR enzymes is typically in the 15-30% range; they 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 15-hydroxyprostaglandin dehydrogenase numbering). In addition to the Tyr and Lys, there is often an upstream Ser and/or an Asn, 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. In addition to the Rossmann fold core region typical of all SDRs, extended SDRs have a less conserved C-terminal extension of approximately 100 amino acids, 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 ketoacyl reductases have a TGXXXGX(1-2)G NAD(P)-binding motif.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371   8 ILVIGGTGHIGKLIIEASVKAGHSTLALVReaslsDPNkgKTVQNFKDFGVTLLHGDLNDHESLVKAIKQADVVISTVGS 87
Cdd:cd05245    1 VLVTGATGYVGGRLVPRLLQEGHQVRALVR-----SPE--KLADRPWSERVTVVRGDLEDPESLRAALEGIDTAYYLVHS 73

                 ..
gi 240254371  88 MQ 89
Cdd:cd05245   74 MG 75

NmrA (a transcriptional regulator), HSCARG (an NADPH sensor), and triphenylmethane reductase (TMR) like proteins, atypical (a) SDRs; Atypical SDRs belonging to this subgroup include NmrA, HSCARG, and TMR, these proteins bind NAD(P) but they lack the usual catalytic residues of the SDRs. Atypical SDRs are distinct from classical SDRs. NmrA is a negative transcriptional regulator of various fungi, involved in the post-translational modulation of the GATA-type transcription factor AreA. NmrA lacks the canonical GXXGXXG NAD-binding motif and has altered residues at the catalytic triad, including a Met instead of the critical Tyr residue. NmrA may bind nucleotides but appears to lack any dehydrogenase activity. HSCARG has been identified as a putative NADP-sensing molecule, and redistributes and restructures in response to NADPH/NADP ratios. Like NmrA, it lacks most of the active site residues of the SDR family, but has an NAD(P)-binding motif similar to the extended SDR family, GXXGXXG. TMR, an NADP-binding protein, lacks the active site residues of the SDRs but has a glycine rich NAD(P)-binding motif that matches the extended SDRs. Atypical SDRs include biliverdin IX beta reductase (BVR-B,aka flavin reductase), NMRa (a negative transcriptional regulator of various fungi), progesterone 5-beta-reductase like proteins, phenylcoumaran benzylic ether and pinoresinol-lariciresinol reductases, phenylpropene synthases, eugenol synthase, triphenylmethane reductase, isoflavone reductases, and others. SDRs are a functionally diverse family of oxidoreductases that have a single domain with a structurally conserved Rossmann fold, an NAD(P)(H)-binding region, and a structurally diverse C-terminal region. Sequence identity between different SDR enzymes is typically in the 15-30% range; they 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 15-hydroxyprostaglandin dehydrogenase numbering). In addition to the Tyr and Lys, there is often an upstream Ser and/or an Asn, 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. In addition to the Rossmann fold core region typical of all SDRs, extended SDRs have a less conserved C-terminal extension of approximately 100 amino acids, 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 ketoacyl reductases have a TGXXXGX(1-2)G NAD(P)-binding motif.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371   8 ILVIGGTGHIGKLIIEASVKAG-HSTLALVREAslsdpnKGKTVQnfKDFGVTLLHGDLNDHESLVKAIKQADVVISTVG 86
Cdd:cd08947    1 IAVTGATGQQGGSVIRHLLAKGaSQVRAVVRNV------EKAATL--ADQGVEVRQGDYNQPELLQKAFAGASKLFIITG 72

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371  87 SMQilDQTKIISAIKEAGNVKRflpsEFGMDVDKSS----AVEPAKSAFGRKLQTRRDIEAEGIPYTYLvtnyFAGYYLP 162
Cdd:cd08947   73 PHY--DNTLEIKQGKNVADAAR----RAGVKHIYSTgyafAEESAIPLAHVKLAVEYAIRTTGIPYTFL----RNGLYTE 142

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371 163 TLVQLepGLTSPPRDKVKI---FGDGNVKAVINKEEDIAAYTIkaVDDPRTLNKTLYINPPnNTLSMNEIVTLWEKKIGK 239
Cdd:cd08947  143 NFVSE--GLPAADTGSGAIvlpAGDGPVPSVTRNDLGPAAAQL--LKEEGHEGKTINLVSN-CRWTPDELAAALSRVLGK 217

                 ..
gi 240254371 240 SV 241
Cdd:cd08947  218 KV 219

Uncharacterized conserved protein, related to short-chain dehydrogenases [Function unknown];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371   1 MASEKSKILVIGGTGHIGKLIIEASVKAGHsTLALV-ReaslsdpNKGKTVQNFKDFG---VTLLHGDLNDHESLVKAIK 76
Cdd:COG3268    1 MTEREFDIVVYGATGYTGRLVAEYLARRGL-RPALAgR-------NAAKLEAVAAELGaadLPLRVADLDDPASLAALLA 72

                         90
                 ....*....|
gi 240254371  77 QADVVISTVG 86
Cdd:COG3268   73 GTRVVLNTVG 82

Pseudomonas fluorescens MupV-like, extended (e) SDRs; This subgroup of extended SDR family domains have the characteristic active site tetrad and a well-conserved NAD(P)-binding motif. This subgroup is not well characterized, its members are annotated as having a variety of putative functions. One characterized member is Pseudomonas fluorescens MupV a protein involved in the biosynthesis of Mupirocin, a polyketide-derived antibiotic. Extended SDRs are distinct from classical SDRs. In addition to the Rossmann fold (alpha/beta folding pattern with a central beta-sheet) core region typical of all SDRs, extended SDRs have a less conserved C-terminal extension of approximately 100 amino acids. Extended SDRs are a diverse collection of proteins, and include isomerases, epimerases, oxidoreductases, and lyases; they typically have a TGXXGXXG cofactor binding motif. SDRs are a functionally diverse family of oxidoreductases that have a single domain with a structurally conserved Rossmann fold, an NAD(P)(H)-binding region, and a structurally diverse C-terminal region. Sequence identity between different SDR enzymes is typically in the 15-30% range; they 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 15-hydroxyprostaglandin dehydrogenase numbering). In addition to the Tyr and Lys, there is often an upstream Ser and/or an Asn, 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. Atypical SDRs generally lack the catalytic residues characteristic of the SDRs, and their glycine-rich NAD(P)-binding motif is often different from the forms normally seen in classical or extended SDRs. 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 ketoacyl reductases have a TGXXXGX(1-2)G NAD(P)-binding motif.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371   8 ILVIGGTGHIGKLIIEASVKAGHSTLALVREASLSDPNKGKTVQNFKDFGVTLLHGDLN------DHESLVKAIKQADVV 81
Cdd:cd05263    1 VFVTGGTGFLGRHLVKRLLENGFKVLVLVRSESLGEAHERIEEAGLEADRVRVLEGDLTqpnlglSAAASRELAGKVDHV 80

                         90       100
                 ....*....|....*....|.
gi 240254371  82 ISTVGSM------QILDQTKI 96
Cdd:cd05263   81 IHCAASYdfqapnEDAWRTNI 101

aldehyde reductase, extended (e) SDRs; This subgroup contains aldehyde reductase of the extended SDR-type and related proteins. Aldehyde reductase I (aka carbonyl reductase) is an NADP-binding SDR; it has an NADP-binding motif consensus that is slightly different from the canonical SDR form and lacks the Asn of the extended SDR active site tetrad. Aldehyde reductase I catalyzes the NADP-dependent reduction of ethyl 4-chloro-3-oxobutanoate to ethyl (R)-4-chloro-3-hydroxybutanoate. Extended SDRs are distinct from classical SDRs. In addition to the Rossmann fold (alpha/beta folding pattern with a central beta-sheet) core region typical of all SDRs, extended SDRs have a less conserved C-terminal extension of approximately 100 amino acids. Extended SDRs are a diverse collection of proteins, and include isomerases, epimerases, oxidoreductases, and lyases; they typically have a TGXXGXXG cofactor binding motif. SDRs are a functionally diverse family of oxidoreductases that have a single domain with a structurally conserved Rossmann fold, an NAD(P)(H)-binding region, and a structurally diverse C-terminal region. Sequence identity between different SDR enzymes is typically in the 15-30% range; they 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 15-hydroxyprostaglandin dehydrogenase numbering). In addition to the Tyr and Lys, there is often an upstream Ser and/or an Asn, 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. Atypical SDRs generally lack the catalytic residues characteristic of the SDRs, and their glycine-rich NAD(P)-binding motif is often different from the forms normally seen in classical or extended SDRs. 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 ketoacyl reductases have a TGXXXGX(1-2)G NAD(P)-binding motif.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 240254371   7 KILVIGGTGHIGKLIIEASVKAGHSTLALVREASLSDPNKGKTVQNFKDFGVTLLHGDL-NDHESLVKAIKQADVVISTV 85
Cdd:cd05227    1 LVLVTGATGFIASHIVEQLLKAGYKVRGTVRSLSKSAKLKALLKAAGYNDRLEFVIVDDlTAPNAWDEALKGVDYVIHVA 80