1YDN,2FTP,1YDO,2CW6


Conserved Protein Domain Family
DRE_TIM_HMGL

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cd07938: DRE_TIM_HMGL 
Click on image for an interactive view with Cn3D
3-hydroxy-3-methylglutaryl-CoA lyase, catalytic TIM barrel domain
3-hydroxy-3-methylglutaryl-CoA lyase (HMGL) catalyzes the cleavage of HMG-CoA to acetyl-CoA and acetoacetate, one of the terminal steps in ketone body generation and leucine degradation, and is a key enzyme in the pathway that supplies metabolic fuel to extrahepatic tissues. Mutations in HMGL cause a human autosomal recessive disorder called primary metabolic aciduria that affects ketogenesis and leucine catabolism and can be fatal due to an inability to tolerate hypoglycemia. HMGL has a TIM barrel domain with a catalytic center containing a divalent cation-binding site formed by a cluster of invariant residues that cap the core of the barrel. The cleavage of HMG-CoA requires the presence of a divalent cation like Mg2+ or Mn2+, and the reaction is thought to involve general acid/base catalysis. This family belongs to the DRE-TIM metallolyase superfamily. DRE-TIM metallolyases include 2-isopropylmalate synthase (IPMS), alpha-isopropylmalate synthase (LeuA), 3-hydroxy-3-methylglutaryl-CoA lyase, homocitrate synthase, citramalate synthase, 4-hydroxy-2-oxovalerate aldolase, re-citrate synthase, transcarboxylase 5S, pyruvate carboxylase, AksA, and FrbC. These members all share a conserved triose-phosphate isomerase (TIM) barrel domain consisting of a core beta(8)-alpha(8) motif with the eight parallel beta strands forming an enclosed barrel surrounded by eight alpha helices. The domain has a catalytic center containing a divalent cation-binding site formed by a cluster of invariant residues that cap the core of the barrel. In addition, the catalytic site includes three invariant residues - an aspartate (D), an arginine (R), and a glutamate (E) - which is the basis for the domain name "DRE-TIM".
Statistics
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PSSM-Id: 163676
View PSSM: cd07938
Aligned: 293 rows
Threshold Bit Score: 294.3
Threshold Setting Gi: 226364405
Created: 11-Sep-2009
Updated: 2-Oct-2020
Structure
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Program:
Drawing:
Aligned Rows:
 
Conserved site includes 9 residues -Click on image for an interactive view with Cn3D
Feature 1:active site [active site]
Evidence:
  • Structure:2CW6_A; Homo sapiens 3-hydroxy-3-methylglutaryl-CoA lyase binds Mg2+ the dicarboxylic acid 3-hydroxyglutarate, contacts at 4A.
    View structure with Cn3D
  • Structure:1YDN_A; Brucella melitensis 3-hydroxy-3-methylglutaryl-CoA lyase binds Ca2+.
    View structure with Cn3D

Sequence Alignment
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Format: Row Display: Color Bits: Type Selection:
Feature 1             ##  #                             # #                                     
1YDN_A        7 IVEXAARDGLQNEkrfvpTADKIALINRLSDCGYARIEATSFVSPKWVPQLADSREVXAGIRRad-----gvRYSVLVPN 81  Brucella meliten...
2CW6_A        8 IVEVGPRDGLQNEknivsTPVKIKLIDMLSEAGLSVIETTSFVSPKWVPQMGDHTEVLKGIQKfp-----giNYPVLTPN 82  human
ZP_03496043   5 KWVECPRDAWQGFsrfipTEEKVAFVKNLLEAGFRHLDLTSFVSPRWVPQMADAEEVLKSLPPpe-----grTYLAIVAN 79  Thermus aquaticu...
ZP_04034555   2 RWVECPRDSWQGFrqfipTDEKLAYLRGLLEAGFTHLDLTSFVSPKWVPQHADAEEVLARLPApq-----grEYLVIIAN 76  Meiothermus silv...
YP_590503     6 KIIECPRDAWQGLkgqipTELKVKYLQELVSAGFKHIDAVSFVSPRAVPQMADSEEVLKELDPpd-----dvEIIGIVVN 80  Acidobacteria ba...
ZP_04038671   2 RWVECPRDSWQGFarfipTEEKVGYLLELLEAGFTNLDLTSFVSPKWVPQHADAEAVLAALPApq-----grEYLAIIGN 76  Meiothermus rube...
XP_844420    12 RMVECPRDAMQGLphfipTEQKIRYLKALLKCGFYALDCGSFVSPRAVPQMRDSTEVIANCWKtmqeekaapKLSVVVAS 91  Trypanosoma bruc...
ZP_03854030   2 FLTECPRDAMQGWgefipTDKKIDYINSLMDVGFDVLDCLSFVSPKAIPQMADSNEVAENIDKsrs----ktKVSAIIGN 77  Chryseobacterium...
ZP_01721428   3 KLIECPRDAMQGIphfidTAVKAAYINQLLEIGFDTIDFGSFVSPKAVPQLRDTEEVLGLLDLhha----ksKLLAIVAN 78  Algoriphagus sp....
ZP_03701117   6 KIIECPRDAMQGIktfipTNQKIIYLQSLLNCGFDTLDFGSFVSPKAIPQMSDTSAVLSGLDLnnt----atKLLSIVAN 81  Flavobacteria ba...
Feature 1                         #                                                             
1YDN_A       82 xKGYEAAAAah-adEIAVFISASEGFSKANincti----------------aesiERLSPVIGAAINDGLAIRGYVSCVV 144 Brucella meliten...
2CW6_A       83 lKGFEAAVAag-akEVVIFGAASELFTKKNincsi----------------eesfQRFDAILKAAQSANISVRGYVSCAL 145 human
ZP_03496043  80 eRGLERALKapnltHVGYPFSLSETFQRKNtnrs-----------------leesWPLVKAIVEGTRGRLGLVVYLSMAF 142 Thermus aquaticu...
ZP_04034555  77 eRGMQRALQaenvtSVGYPFSICETFQRKNvnkt-----------------iaesWEELAHMRDMASGRLGFVVYLSMGF 139 Meiothermus silv...
YP_590503    81 eKGADRAIAteavrTLGFPYSFSPTFLKNNqnqtl----------------eenaEVLEKVVEKQRSADMDLVVYISMAF 144 Acidobacteria ba...
ZP_04038671  77 lKGLERARQaahltAVGYPFSISETFQRKNlnlg------------------ieeSWPVLQQLLAEAQGLRFVVYLSMAF 138 Meiothermus rube...
XP_844420    92 lAGFKQALEtpgvsVIGYPIGCCERFQQRNakksiamsldeirnikeatdafnaqRSSNPVAPNEDVNGRELLIYISMAF 171 Trypanosoma bruc...
ZP_03854030  78 yRGAEKALKhqsvdILGFPFSISETFQHRNtnksq----------------eeafDEIIKMLDLVKSEGKQLNIYFSMAF 141 Chryseobacterium...
ZP_01721428  79 lRGAEDASHfdeidYLGFPLSVSETFQQKNtnrsi----------------sealKTVEEIQNLCEVKGKTLVTYLSMGF 142 Algoriphagus sp....
ZP_03701117  82 lRGAEAACShdeisYLGFPFSISENFQMRNthtti----------------teaiTVLQSILDLARKKDKKVVVYLSMGF 145 Flavobacteria ba...
Feature 1                                                                     # #               
1YDN_A      145 ECPYDGpvtpQAVASVTEQLFs-lGCHEVSLGDTIGRGTPDTVAAXLDAVLAIapa-hsLAGHYHDTGGRALDNIRVSLE 222 Brucella meliten...
2CW6_A      146 GCPYEGkispAKVAEVTKKFYs-mGCYEISLGDTIGVGTPGIMKDMLSAVMQEvpl-aaLAVHCHDTYGQALANTLMALQ 223 human
ZP_03496043 143 GNPYGDpwsvEEVLEAVARLRe-lGVEEIALADTYGVAEAATIREVLQAAVARfgp-egLGAHLHARPQGVLKKVEAVLE 220 Thermus aquaticu...
ZP_04034555 140 GNPYGDpwspERVVEFVGQLRe-mGIRRIALADTYGVATAQAIRKTLQAVAVAfgp-edIGAHLHSRPEATLEKVDAVLA 217 Meiothermus silv...
YP_590503   145 GNPYGDlwsvDEVLEGIGILAd-dGIQQISLADTVGLATPQQIADLCGPIVEKfdy-leVGVHLHGTHTDAKEKVLAAYD 222 Acidobacteria ba...
ZP_04038671 139 GNPYGDtwtpGLTAQFVQRMRalpGLSGIVLADTYGVASAQTIAQTLEAVAQAggldehLGLHLHSRPEHTLDKVRVALA 218 Meiothermus rube...
XP_844420   172 GNPYGEshsiDLVEKLVGELVa-sGARDISLADTTGVAQPPLIFDTFTQLRKKfpd-vtFAGHFHSNAVEARGKIVAALD 249 Trypanosoma bruc...
ZP_03854030 142 GNPYGEmwkwEDVDQWAQRFSd-iGVKDILLSDTTGVATPETIALLFEKIPSKype-inFGGHFHNRYEDSYSKLKAAYD 219 Chryseobacterium...
ZP_01721428 143 GNPYDEayspELIAEFVEKLNq-lDLKIISIADTVGKANPELIEKVFEVQTQAfpe-ieFGAHLHSTAAGTKEKVISALK 220 Algoriphagus sp....
ZP_03701117 146 GNPYGDpwstEIVANWVSKLSa-mGVEILSLSDTVGSAQPQDISALYRHLIPAyps-ieFGAHFHTKAAEWYEKVHAAFG 223 Flavobacteria ba...
Feature 1                                 #                                     
1YDN_A      223 KGlRVFDASVGGLGGCPFa--PGAKGNVDTVAVVEXLHexGFETGLDL----DRLRSAGLFTQA 280 Brucella melitensis 16M
2CW6_A      224 MGvSVVDSSVAGLGGCPYa--QGASGNLATEDLVYMLEglGIHTGVNL----QKLLEAGNFICQ 281 human
ZP_03496043 221 AGiTWLEGALAGVGGCPFa-gDELIGNLPTEVVLPYLErrGLRTGVDL----ARLPLLAEEAAR 279 Thermus aquaticus Y51MC23
ZP_04034555 218 SGvRWLEGALAGIGGCPFa-gDDLVGNLATEAVLPYLArkGFEVGVQL----DSLAQLADEAAL 276 Meiothermus silvanus DSM 9946
YP_590503   223 AGiRRFDAALGGLGGCPFa-qNTLVGNLPTEAVFTALKerKVEPPVRKp--iDTLLQMSSDFAL 283 Acidobacteria bacterium Ellin345
ZP_04038671 219 SGvGWLEGALGGIGGCPFa-gDDLVGNLATEQVLPYLAqqGRVTGVDL----DRLGELSSRAQL 277 Meiothermus ruber DSM 1279
XP_844420   250 AGcTMIDSALCGMGGCPFakdDGLVGNVATEVVVKALEerGVLPAALNk---EQLKKCVLIKQE 310 Trypanosoma brucei TREU927
ZP_03854030 220 KGcRRFDSAIKGIGGCPMa-kDDLVGNMPTEQVINFMSveKVEHKLNLln-fESSYNKAKDIFH 281 Chryseobacterium gleum ATCC 35910
ZP_01721428 221 GGcKRFDGALNGYGGCPFa-eNELVGNVATEILIDTLEgeGHELIINKaelkEALKLTGFVFSE 283 Algoriphagus sp. PR1
ZP_03701117 224 SGcLRFDGAIQGFGGCPMa-aDALTGNMPTEKLLSYFTskKVAHGVKW----MAFEAAHNKATA 282 Flavobacteria bacterium MS024-3C

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