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 215736991  80 KIVVLGGSGFVGSAICKAAVSKGIEVVSLSRSGRPSYS-DPWVDQVtwLAGDVfyaRWDEVL----VGATAVVSTLGGFG 154
Cdd:cd05243    1 KVLVVGATGKVGRHVVRELLDRGYQVRALVRDPSQAEKlEAAGAEV--VVGDL---TDAESLaaalEGIDAVISAAGSGG 75

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 215736991 155 NE-EQMKRINGEANVTAVDAAKEFGIPKFILISVHDYNLPSFLLNS--GYFTGKRKAESEVLskypTSGV---VLRPG 226
Cdd:cd05243   76 KGgPRTEAVDYDGNINLIDAAKKAGVKRFVLVSSIGADKPSHPLEAlgPYLDAKRKAEDYLR----ASGLdytIVRPG 149

sugar epimerase family protein;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 215736991  80 KIVVLGGSGFVGSAICKAAVSKGIEVVSLSRSgRPsysDPWVDQVTWLAGDVFYARWDEVLVGATAVVSTLGGFGNEEQM 159
Cdd:PRK05865   2 RIAVTGASGVLGRGLTARLLSQGHEVVGIARH-RP---DSWPSSADFIAADIRDATAVESAMTGADVVAHCAWVRGRNDH 77

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|..
gi 215736991 160 KRINGEANVtaVDAAKEFGIPKFILISV-HDYNLPSFLLNSG 200
Cdd:PRK05865  78 INIDGTANV--LKAMAETGTGRIVFTSSgHQPRVEQMLADCG 117

Nucleoside-diphosphate-sugar epimerase [Cell wall/membrane/envelope biogenesis];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 215736991  80 KIVVLGGSGFVGSAICKAAVSKGIEVVSLSRSGRPSYSDPWVDQVTWLAGDVF-YARWDEVLVGATAVV----STLGGFG 154
Cdd:COG0451    1 RILVTGGAGFIGSHLARRLLARGHEVVGLDRSPPGAANLAALPGVEFVRGDLRdPEALAAALAGVDAVVhlaaPAGVGEE 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 215736991 155 NEEQMKRINGEANVTAVDAAKEFGIPKFILIS----VHDYNLP-----SFLLNSGYFTGKRKAESEVLS---KYPTSGVV 222
Cdd:COG0451   81 DPDETLEVNVEGTLNLLEAARAAGVKRFVYASsssvYGDGEGPidedtPLRPVSPYGASKLAAELLARAyarRYGLPVTI 160

                        170
                 ....*....|
gi 215736991 223 LRPGFIYGKR 232
Cdd:COG0451  161 LRPGNVYGPG 170

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 215736991  80 KIVVLGGSGFVGSAICKAAVSKGIEVVSLSRSGRPSYS-DPWVDQVtwLAGDVfyaRWDEVL----VGATAVVSTLGGFG 154
Cdd:cd05243    1 KVLVVGATGKVGRHVVRELLDRGYQVRALVRDPSQAEKlEAAGAEV--VVGDL---TDAESLaaalEGIDAVISAAGSGG 75

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 215736991 155 NE-EQMKRINGEANVTAVDAAKEFGIPKFILISVHDYNLPSFLLNS--GYFTGKRKAESEVLskypTSGV---VLRPG 226
Cdd:cd05243   76 KGgPRTEAVDYDGNINLIDAAKKAGVKRFVLVSSIGADKPSHPLEAlgPYLDAKRKAEDYLR----ASGLdytIVRPG 149

NAD(P)H-binding;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 215736991   85 GGSGFVGSAICKAAVSKGIEVVSLSR--SGRPSYSDPwvDQVTWLAGDVF-YARWDEVLVGATAVVSTLGGFGNEEQMkr 161
Cdd:pfam13460   1 GATGKIGRLLVKQLLARGHEVTALVRnpEKLADLEDH--PGVEVVDGDVLdPDDLAEALAGQDAVISALGGGGTDETG-- 76

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 215736991  162 ingeaNVTAVDAAKEFGIPKFILIS---VHDYNLPSFLLNS-----GYFTGKRKAEsEVLSkypTSG---VVLRPGFIY 229
Cdd:pfam13460  77 -----AKNIIDAAKAAGVKRFVLVSslgVGDEVPGPFGPWNkemlgPYLAAKRAAE-ELLR---ASGldyTIVRPGWLT 146

CC3(TIP30)-like, atypical (a) SDRs; Atypical SDRs in this subgroup include CC3 (also known as TIP30) which is implicated in tumor suppression. Atypical SDRs are distinct from classical SDRs. Members of this subgroup have a glycine rich NAD(P)-binding motif that resembles the extended SDRs, and have an active site triad of the SDRs (YXXXK and upstream Ser), although the upstream Asn of the usual SDR active site is substituted with Asp. For CC3, the Tyr of the triad is displaced compared to the usual SDRs and the protein is monomeric, both these observations suggest that the usual SDR catalytic activity is not present. NADP appears to serve an important role as a ligand, and may be important in the interaction with other macromolecules. 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 215736991  83 VLGGSGFVGSAICKAAVSKGI--EVVSLSRsgRP---SYSDPWVDQVTwlagdVFYARWDEVL-------VGATAVVSTL 150
Cdd:cd05250    5 VLGATGLVGKHLLRELLKSPYysKVTAIVR--RKltfPEAKEKLVQIV-----VDFERLDEYLeafqnpdVGFCCLGTTR 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 215736991 151 GGFGNEEQMKRINGEANVTAVDAAKEFGIPKFILISVHDYNLPSFLLnsgYFTGKRKAESEVLSKYPTSGVVLRPGFIYG 230
Cdd:cd05250   78 KKAGSQENFRKVDHDYVLKLAKLAKAAGVQHFLLVSSLGADPKSSFL---YLKVKGEVERDLQKLGFERLTIFRPGLLLG 154

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 215736991 231 KRKvdgfeipldvVGQPLEKLlssVENFTKPLSSLPASDLLlapPVSVDDVAYAVINGVIDDS 293
Cdd:cd05250  155 ERQ----------ESRPGERL---AQKLLRILSPLGFPKYK---PIPAETVAKAMVKAALKES 201

uncharacterized subgroup of aldehyde reductase and flavonoid reductase related proteins, extended (e) SDRs; This subgroup contains proteins of unknown function related to aldehyde reductase and flavonoid reductase of the extended SDR-type. 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. The related flavonoid reductases act in the NADP-dependent reduction of flavonoids, ketone-containing plant secondary metabolites. 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 215736991  81 IVVLGGSGFVGSAICKAAVSKGIEVVSLSRSGRPSYSDPWVDqVTWLAGDVF-YARWDEVLVGATAVVSTLGGF----GN 155
Cdd:cd05228    1 ILVTGATGFLGSNLVRALLAQGYRVRALVRSGSDAVLLDGLP-VEVVEGDLTdAASLAAAMKGCDRVFHLAAFTslwaKD 79

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 215736991 156 EEQMKRINGEANVTAVDAAKEFGIPKFILIS------VHD-------YNLPSFLLNSGYFTGKRKAESEVLsKYPTSG-- 220
Cdd:cd05228   80 RKELYRTNVEGTRNVLDAALEAGVRRVVHTSsiaalgGPPdgridetTPWNERPFPNDYYRSKLLAELEVL-EAAAEGld 158

                        170
                 ....*....|..
gi 215736991 221 -VVLRPGFIYGK 231
Cdd:cd05228  159 vVIVNPSAVFGP 170

Extended (e) and atypical (a) SDRs; Extended or atypical short-chain dehydrogenases/reductases (SDRs, aka tyrosine-dependent oxidoreductases) 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. 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. 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 215736991  81 IVVLGGSGFVGSAICKAAVSKGIEVVSLSRSGRPSYSDPW--VDQVTWLAGDVfyARWDEVLVGATAVVSTLG----GFG 154
Cdd:cd05226    1 ILILGATGFIGRALARELLEQGHEVTLLVRNTKRLSKEDQepVAVVEGDLRDL--DSLSDAVQGVDVVIHLAGaprdTRD 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 215736991 155 NEEQMkrINGEANVtaVDAAKEFGIPKFILIS-VHDY-NLPSFLLNSGY-FTGKRKAESE-VLSKYPTSGVVLRPGFIYG 230
Cdd:cd05226   79 FCEVD--VEGTRNV--LEAAKEAGVKHFIFISsLGAYgDLHEETEPSPSsPYLAVKAKTEaVLREASLPYTIVRPGVIYG 154

UDP-glucose 4-epimerase (G4E), subgroup 5, extended (e) SDRs; This subgroup partially conserves the characteristic active site tetrad and NAD-binding motif of the extended SDRs, and has been identified as possible UDP-glucose 4-epimerase (aka UDP-galactose 4-epimerase), a homodimeric member of the extended SDR family. UDP-glucose 4-epimerase catalyzes the NAD-dependent conversion of UDP-galactose to UDP-glucose, the final step in Leloir galactose synthesis. 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 215736991  80 KIVVLGGSGFVGSAICKAAVSKGIEVVSLSRSGRPSYSDPWvdQVTWLAGDvFYARWD--EVLVGATAVV----STLGGF 153
Cdd:cd05264    1 RVLIVGGNGFIGSHLVDALLEEGPQVRVFDRSIPPYELPLG--GVDYIKGD-YENRADleSALVGIDTVIhlasTTNPAT 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 215736991 154 GNEEQMKRIngEANVTA----VDAAKEFGIPKFILIS-------VHDYnLP-----SFLLNSGYFTGKRKAESEVL---S 214
Cdd:cd05264   78 SNKNPILDI--QTNVAPtvqlLEACAAAGIGKIIFASsggtvygVPEQ-LPisesdPTLPISSYGISKLAIEKYLRlyqY 154

                        170
                 ....*....|....*...
gi 215736991 215 KYPTSGVVLRPGFIYGKR 232
Cdd:cd05264  155 LYGLDYTVLRISNPYGPG 172

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 215736991  80 KIVVLGGSGFVGSAICKAAV-SKGIEVVSLSRSGRPSYSDPWVDQVTWLAGDVFY-ARWDEVLVGATAVVSTLGGFGNEE 157
Cdd:cd05259    1 KIAIAGATGTLGGPIVSALLaSPGFTVTVLTRPSSTSSNEFQPSGVKVVPVDYAShESLVAALKGVDAVISALGGAAIGD 80

                         90       100
                 ....*....|....*....|....*.
gi 215736991 158 QMKringeanvtAVDAAKEFGIPKFI 183
Cdd:cd05259   81 QLK---------LIDAAIAAGVKRFI 97

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 215736991  80 KIVVLGGSGFVGSAICKAAVSKGIEVVSLSRsGRPSYSDPwvDQVTWLAGD------VFYAR----WDEVL--VGATA-- 145
Cdd:cd05265    2 KILIIGGTRFIGKALVEELLAAGHDVTVFNR-GRTKPDLP--EGVEHIVGDrndrdaLEELLggedFDVVVdtIAYTPrq 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 215736991 146 VVSTLGGFGNeeqmkRINGEANVTAVDAAKEFGIPKFILISVHDYNLPSFLLNSGYFTGKRKAESEVLSKYPTSGVVLRP 225
Cdd:cd05265   79 VERALDAFKG-----RVKQYIFISSASVYLKPGRVITESTPLREPDAVGLSDPWDYGRGKRAAEDVLIEAAAFPYTIVRP 153

                 ....*
gi 215736991 226 GFIYG 230
Cdd:cd05265  154 PYIYG 158

atypical (a) SDRs, subgroup 8; This subgroup contains atypical SDRs of unknown function. Proteins in this subgroup have a glycine-rich NAD(P)-binding motif consensus that resembles that of the extended SDRs, (GXXGXXG or GGXGXXG), but lacks the characteristic active site residues of the SDRs. A Cys often replaces the usual Lys of the YXXXK active site motif, while the upstream Ser is generally present and Arg replaces the usual Asn. 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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 215736991  80 KIVVLGGSGFVGSAICKAAVSKGIEVVSLSRSGRPSYSDPWVdqVTW--LAGDvfyarwDEVLVGATAVV 147
Cdd:cd05242    1 KIVITGGTGFIGRALTRRLTAAGHEVVVLSRRPGKAEGLAEV--ITWdgLSLG------PWELPGADAVI 62

3beta-hydroxysteroid dehydrogenases (3b-HSD)-like, extended (e) SDRs; Extended SDR family domains belonging to this subgroup have the characteristic active site tetrad and a fairly well-conserved NAD(P)-binding motif. 3b-HSD catalyzes the NAD-dependent conversion of various steroids, such as pregnenolone to progesterone, or androstenediol to testosterone. This subgroup includes an unusual bifunctional 3b-HSD/C-4 decarboxylase from Arabidopsis thaliana, and Saccharomyces cerevisiae ERG26, a 3b-HSD/C-4 decarboxylase, involved in the synthesis of ergosterol, the major sterol of yeast. It also includes human 3 beta-HSD/HSD3B1 and C(27) 3beta-HSD/ [3beta-hydroxy-delta(5)-C(27)-steroid oxidoreductase; HSD3B7]. C(27) 3beta-HSD/HSD3B7 is a membrane-bound enzyme of the endoplasmic reticulum, that catalyzes the isomerization and oxidation of 7alpha-hydroxylated sterol intermediates, an early step in bile acid biosynthesis. Mutations in the human NSDHL (NAD(P)H steroid dehydrogenase-like protein) cause CHILD syndrome (congenital hemidysplasia with ichthyosiform nevus and limb defects), an X-linked dominant, male-lethal trait. Mutations in the human gene encoding C(27) 3beta-HSD underlie a rare autosomal recessive form of neonatal cholestasis. 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 sythase 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 215736991  81 IVVLGGSGFVGSAICKAAVSK-GIEVVSLSRSGRPSYSDPW-VDQVTWLAGDVFYArwDEVLV---GATAV---VSTLGG 152
Cdd:cd05241    2 VLVTGGSGFFGERLVKQLLERgGTYVRSFDIAPPGEALSAWqHPNIEFLKGDITDR--NDVEQalsGADCVfhtAAIVPL 79

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 215736991 153 FGNEEQMKRIN--GEANVtaVDAAKEFGIPKFILIS----------VH--DYNLPSF-LLNSGYFTGKRKAESEVLSKYP 217
Cdd:cd05241   80 AGPRDLYWEVNvgGTQNV--LDACQRCGVQKFVYTSsssvifggqnIHngDETLPYPpLDSDMYAETKAIAEIIVLEANG 157

                        170       180       190
                 ....*....|....*....|....*....|....*...
gi 215736991 218 TSG---VVLRPGFIYGKRKVDGFEIPLDVVGQPLEKLL 252
Cdd:cd05241  158 RDDlltCALRPAGIFGPGDQGLVPILFEWAEKGLVKFV 195

UDP-glucose 4 epimerase (G4E), subgroup 3, extended (e) SDRs; Members of this bacterial subgroup are identified as possible sugar epimerases, such as UDP-glucose 4 epimerase. However, while the NAD(P)-binding motif is fairly well conserved, not all members retain the canonical active site tetrad of the extended SDRs. UDP-glucose 4 epimerase (aka UDP-galactose-4-epimerase), is a homodimeric extended SDR. It catalyzes the NAD-dependent conversion of UDP-galactose to UDP-glucose, the final step in Leloir galactose synthesis. 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 215736991  81 IVVLGGSGFVGSAICK--AAVSKGIEVVSLSRSGRPsysdPWVDQVTWLAGDVFYARWDEVLV--GATAVV---STLGGF 153
Cdd:cd05240    1 ILVTGAAGGLGRLLARrlAASPRVIGVDGLDRRRPP----GSPPKVEYVRLDIRDPAAADVFRerEADAVVhlaFILDPP 76

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 215736991 154 GNEEQMKRINGEANVTAVDAAKEFGIPKFILIS-VHDY----NLPSFLLN---------SGYFTGKRKAE---SEVLSKY 216
Cdd:cd05240   77 RDGAERHRINVDGTQNVLDACAAAGVPRVVVTSsVAVYgahpDNPAPLTEdaplrgspeFAYSRDKAEVEqllAEFRRRH 156

                        170
                 ....*....|....*
gi 215736991 217 PTSGV-VLRPGFIYG 230
Cdd:cd05240  157 PELNVtVLRPATILG 171

CDP-tyvelose 2-epimerase, extended (e) SDRs; CDP-tyvelose 2-epimerase is a tetrameric SDR that catalyzes the conversion of CDP-D-paratose to CDP-D-tyvelose, the last step in tyvelose biosynthesis. This subgroup is a member of the extended SDR subfamily, with a characteristic active site tetrad and NAD-binding motif. 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
                 ....*....|....*....|....*....|....*..
gi 215736991  79 EKIVVLGGSGFVGSAICKAAVSKGIEVV---SLSRSG 112
Cdd:cd05258    1 MRVLITGGAGFIGSNLARFFLKQGWEVIgfdNLMRRG 37

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 215736991  81 IVVLGGSGFVGSAICKAAVSKGIEVVSLSRSGRPSYSDPWVDQVTWLAGDVFY-ARWDEVLVGATAV---VSTLGGFGNE 156
Cdd:cd05245    1 VLVTGATGYVGGRLVPRLLQEGHQVRALVRSPEKLADRPWSERVTVVRGDLEDpESLRAALEGIDTAyylVHSMGSGGDF 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 215736991 157 EQMKRingEANVTAVDAAKEFGIPKFILIS--VHDYNLPSFLLNSgyftgkRKAESEVLSKYPTSGVVLRPGFIYG 230
Cdd:cd05245   81 EEADR---RAARNFARAARAAGVKRIIYLGglIPKGEELSPHLRS------RAEVGEILRAGGVPVTELRAAVIIG 147

UDP-N-acetylglucosamine 4-epimerase, extended (e) SDRs; This subgroup contains UDP-N-acetylglucosamine 4-epimerase of Pseudomonas aeruginosa, WbpP, an extended SDR, that catalyzes the NAD+ dependent conversion of UDP-GlcNAc and UDPGalNA to UDP-Glc and UDP-Gal. This subgroup has the characteristic active site tetrad and NAD-binding motif of the extended SDRs. 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 215736991  80 KIVVLGGSGFVGSAICKAAVSKGIEVV---SLSrSGRPSYSDPWVDQVTWLAGDVFYARWDEVLVGATAVVSTLGGFGN- 155
Cdd:cd05256    1 RVLVTGGAGFIGSHLVERLLERGHEVIvldNLS-TGKKENLPEVKPNVKFIEGDIRDDELVEFAFEGVDYVFHQAAQASv 79

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 215736991 156 ----EEQMKriNGEANVTA----VDAAKEFGIPKFILIS 186
Cdd:cd05256   80 prsiEDPIK--DHEVNVLGtlnlLEAARKAGVKRFVYAS 116

NmrA-like family; NmrA is a negative transcriptional regulator involved in the post-translational modification of the transcription factor AreA. NmrA is part of a system controlling nitrogen metabolite repression in fungi. This family only contains a few sequences as iteration results in significant matches to other Rossmann fold families.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 215736991   81 IVVLGGSGFVGSAICKAAVSKGIEVVSLSRSGRPSYSDPWVDQ-VTWLAGDVF-YARWDEVLVGATAVVSTLG-GFGNE- 156
Cdd:pfam05368   1 ILVFGATGQQGGSVVRASLKAGHKVRALVRDPKSELAKSLKEAgVELVKGDLDdKESLVEALKGVDVVFSVTGfWAGKEi 80

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 215736991  157 EQMKRIngeanvtaVDAAKEFGIPKFILISVHDYN 191
Cdd:pfam05368  81 EDGKKL--------ADAAKEAGVKHFIPSSFGNDN 107