1NJE,1F28,2KCE,2AAZ,1HVY,1LCA,1I00,1J3K,2G86,2TSR,1QZF,1BKP


Conserved Protein Domain Family
TS_Pyrimidine_HMase

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cd00351: TS_Pyrimidine_HMase 
Click on image for an interactive view with Cn3D
Thymidylate synthase and pyrimidine hydroxymethylase: Thymidylate synthase (TS) and deoxycytidylate hydroxymethylase (dCMP-HMase) are homologs that catalyze analogous alkylation of C5 of pyrimidine nucleotides. Both enzymes are involved in the biosynthesis of DNA precursors and are active as homodimers. However, they exhibit distinct pyrimidine base specificities and differ in the details of their catalyzed reactions. TS is biologically ubiquitous and catalyzes the conversion of dUMP and methylene-tetrahydrofolate (CH2THF) to dTMP and dihydrofolate (DHF). It also acts as a regulator of its own expression by binding and inactivating its own RNA. Due to its key role in the de novo pathway for thymidylate synthesis and, hence, DNA synthesis, it is one of the most conserved enzymes across species and phyla. TS is a well-recognized target for anticancer chemotherapy, as well as a valuable new target against infectious diseases. Interestingly, in several protozoa, a single polypeptide chain codes for both, dihydrofolate reductase (DHFR) and thymidylate synthase (TS), forming a bifunctional enzyme (DHFR-TS), possibly through gene fusion at a single evolutionary point. DHFR-TS is also active as a dimer. Virus encoded dCMP-HMase catalyzes the reversible conversion of dCMP and CH2THF to hydroxymethyl-dCMP and THF. This family also includes dUMP hydroxymethylase, which is encoded by several bacteriophages that infect Bacillus subtilis, for their own protection against the host restriction system, and contain hydroxymethyl-dUMP instead of dTMP in their DNA.
Statistics
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PSSM-Id: 238211
Aligned: 69 rows
Threshold Bit Score: 139.719
Created: 6-Mar-2002
Updated: 2-Oct-2020
Structure
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Program:
Drawing:
Aligned Rows:
 
active sitedimerization
Conserved site includes 15 residues -Click on image for an interactive view with Cn3D
Feature 1:active site [active site]
Evidence:
  • Comment:Active site residues involved in cofactor and substrate binding, including conserved dimer Arginines, as per pmid12525151
  • Structure:Pneumocystis Carinii 1F28: substrate (dUMP) and inhibitor (BW1843U89) bound
    View structure with Cn3D

Sequence Alignment
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Format: Row Display: Color Bits: Type Selection:
Feature 1                              #                                           #            
1NJE          5 PYLDLAKKVLDEGHfk-----pDRTh---tGTYSIFGh---QMRFdlskgfp-llttkkvPFGLIKSELLWFlhg-dtnI 71  Lactobacillus casei
1F28_B        8 QYLNLVQYIINHGEdr-----pDRTg---tGTLSVFAp--sPLKFslrnktfpllttkrvFIRGVIEELLWFirg-etdS 76  Pneumocystis car...
YP_448257     9 SISQAWLTCVKKIMqeghevtdERGs----LTKELQNv---ILEIt-------------nPNDNTIPECSPWh------D 62  Methanosphaera s...
CAF30935     12 AFEALIPKIMEEGTem----itEDGq----KCKEIMNt---IIEIn-------------dPSDKSISEKYPLg------E 61  Methanococcus ma...
ZP_00515839 198 TIAETWVKILQRIKt-------TGT-----IRPTQYGq---WQELidmtai---vtdeplNFYFPSPNYLPI-------K 252 Crocosphaera wat...
Q57931       12 AFNELIPKILKDGEv-------VETef-eeRTKEIRNt---IIEIt-------------nPKLKKVPEKYPLg------E 61  Methanocaldococc...
NP_070871    18 SLADFFSICLAMLKrfs---maDKTf----FHGKLFNllrkWVLMilt----------ktPEEAKEMLVSKVigg-etcR 79  Archaeoglobus fu...
Q8TVL9       14 TVEQVWRQAVTGIKvhgekverERG-----PVKEVRGl---IAHLep-----------sgPESFDIPDDYPLd------E 68  Methanopyrus kan...
AAW39954     10 DLSEAWFLCLRQVLtdgyeytiERGsytgqKRKELDMi---TVHIk-------------nPGNRPLIPDVPPgvpapstL 73  Dehalococcoides ...
CAJ35309     14 SIAKAWEWAIGKIYreg---qlVNTey-gvKARMVNGm---LLEIa-------------nPVQKWHPKDPFCs------P 67  uncultured metha...
Feature 1                      #  #                                                            #
1NJE         72 RFLLQHr-----nHIWDEWafekwvksdeyhgpdmtdfghrsqkdpefaavyheemakfddrvlhddafaakygdLGLVY 146 Lactobacillus casei
1F28_B       77 LKLREKn-----iHIWDANgsreyldsi--------------------------------------gltkrqegdLGPIY 113 Pneumocystis car...
YP_448257    63 DRLETYk-----kELLDPDne----------------------------------------------------qgFVYTY 85  Methanosphaera s...
CAF30935     62 RAVKSYt-----eQLLHGSaa-----------------------------------------------------tFVYDY 83  Methanococcus ma...
ZP_00515839 253 REFINDyi----gQILDDApqk---------------------------------------------------egVKYTY 277 Crocosphaera wat...
Q57931       62 KAVEEYtk---nlLYGSKNv-------------------------------------------------------FSYDY 83  Methanocaldococc...
NP_070871    80 SRFGDYrlskptmVVVEEPts----------------------------------------------------fgFEFDY 107 Archaeoglobus fu...
Q8TVL9       69 HSVRAYe-----dQLLDPElr-----------------------------------------------------gFEYTY 90  Methanopyrus kan...
AAW39954     74 EYIDNYl-----pYLMTAHra----------------------------------------------------egEQYTY 96  Dehalococcoides ...
CAJ35309     68 MRVKYYv-----eQFKRESagk---------------------------------------------------hgFEYTY 91  uncultured metha...
Feature 1                                                                        ##             
1NJE        147 GSQWRawhts--------kgdtiDQLGDVIEQIKTHPy-SRRLIVSAWNPEDVpt-----maLPPCHTLYQFYVNd---- 208 Lactobacillus casei
1F28_B      114 GFQWRhfgaeyidcktnyigqgvDQLANIIQKIRTSPy-DRRLILSAWNPADLek-----maLPPCHMFCQFYVHipsnn 187 Pneumocystis car...
YP_448257    86 GNRLRqyf-------------kiDQIDTCIEKLNNCPq-SRRAIAITIDPIQDnk-----vdEIPCLQEIAFLIRd---- 142 Methanosphaera s...
CAF30935     84 HERIFeypndk-------kelknDQIEYIVNKLKEQIn-SRRAVAITWNPYIDqs-----vkDVPCLQIVQFLVRd---- 146 Methanococcus ma...
ZP_00515839 278 GQRLRswf-------------erDQIKQAIDKLISDKd-SSRVVMSLWDVKDYen-----ndSPPCLNHIWVRIVd---- 334 Crocosphaera wat...
Q57931       84 HQRLFeypya---------dekiNQIDYIIEKLNQQKn-SRRAVAITWNPKIDievsrdergSVPCLQLVQFLIRn---- 149 Methanocaldococc...
NP_070871   108 DVCGEkyse-----------rlsRCVESAAEKLRKSPh-TRRASIPLWYPKDHlc------rNPAAITEISFIFHe---- 165 Archaeoglobus fu...
Q8TVL9       91 GHRLRryf-------------glDQVTKIVERLSESNn-TRRAIAVTWDPRRDld-----eeEVPCLTALQLQSDgg--- 148 Methanopyrus kan...
AAW39954     97 GQYLE------------------AQIAKVIKMYRDTGfnTNQAFMTVGNPETLdl------eDPPCLRSIDTRIRy---- 148 Dehalococcoides ...
CAJ35309     92 IDRMVnye-------------gfDQLKWMAEQLKNKRydSKRVQAITWIPRVDcak----keDQPCFQRIWVYPYqn--- 151 uncultured metha...
Feature 1                 ### #      ##                                   # #        
1NJE        209 --gKLSLQLYQRSADIflGVPFNIASYALLTHLVAHECGl------EVGEFIHTFGDAHLYVNHLDQIK 269 Lactobacillus casei
1F28_B      188 hrpELSCQLYQRSCDMglGVPFNIASYALLTCMIAHVCDl------DPGDFIHVMGDCHIYKDHIEALQ 250 Pneumocystis carinii
YP_448257   143 --nQLYMTDFFRSNDCggATFPNLFGIREVGYYVAKNTDt------ELVNMVHHAMSLHIYEHDWDKCR 203 Methanosphaera stadtmanae D...
CAF30935    147 --nKLYQTVLFRSNDAflAFHANAIGLIALGEMVAEKLGi------ELVKYTHHSVSMHVYSERDIDNL 207 Methanococcus maripaludis S2
ZP_00515839 335 --dELSLTATFRSNDMfsAWPANAMGLRELQQHIIEEVNnkyqhnfQLGPLIIISQSAHIYSDCWEHAD 401 Crocosphaera watsonii WH 8501
Q57931      150 --gKLYQTVIFRSNDAllAFVSNAIGLITLGEYIAKKVGv------GYGTYTHHAISMHIYVDRDFDYI 210 Methanocaldococcus jannaschii
NP_070871   166 ---KLHLTAFLRSMEClsYFEHNFDFLVEALETICRKTGm------EEGSIGMLIAVPHFYERDVERAL 225 Archaeoglobus fulgidus DSM ...
Q8TVL9      149 --sGLELHAFYRSWDVgkALVANMIALRRLQEHVAERAGl------EPTTLTVYAANAHVYEEDLPDLP 209 Methanopyrus kandleri
AAW39954    149 --gKLHFVIYFRSWDLwaGFPSNLAAIQMLKEYMAAEIGv------EDGEIIAMSKGMHIYDYAWDIAK 209 Dehalococcoides ethenogenes...
CAJ35309    152 --dTLDVHIHYRSWDMfkAFEANLMAFQELVKDELTGPSg-----fTLGKLRCFGDNVHIYEDDFQAVE 213 uncultured methanogenic arc...

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