4FZB,4KAR,5IOS,3N0B,2AF6,4P5A,4FZB,3AH5


Conserved Protein Domain Family
ThyX

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cd20175: ThyX 
FAD-dependent thymidylate synthase (ThyX), mechanistically and structurally unrelated to thymidylate synthase (ThyA)
This family contains FAD-dependent thymidylate synthase (also known as ThyX, Thy1, FDTS or thymidylate synthase complementing protein), found in many microbial genomes including several human pathogens, but absent in humans. This protein is mechanistically and structurally unrelated to thymidylate synthase (TS or ThyA) found in mammals. ThyA and ThyX both produce de novo thymidylate or deoxythymidine 5'-monophosphate (dTMP), an essential DNA precursor. The classic ThyA catalyzes the reductive methylation of deoxyuridine 5'-monophosphate (dUMP) to form dTMP, with methylenetetrahydrofolate (CH2H4folate) serving as a one-carbon donor and as the source of reductive power. On the other hand, ThyX contains FAD, tightly bound by a novel fold, that mediates hydride transfer from NADPH during catalysis. Consequently, CH2H4folate serves only as a carbon donor and tetrahydrofolate (and not dihydrofolate as in the case of ThyA) is produced. The differences between the ThyX and ThyA is used for mechanism-based drugs to selectively inhibit FDTS and not have much effect on human and other eukaryotic TS. ThyX has been pursued for the development of new antibacterial agents against Mycobacterium tuberculosis, the causative agent of the widespread infectious disease tuberculosis (TB). It is also an attractive target for designing specific antibiotic drugs against many diseases such as ulcers, periodontal disease, and Lyme's disease, as well as biological warfare agents such as anthrax, botulism, and typhus.
Statistics
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PSSM-Id: 412038
Aligned: 363 rows
Threshold Bit Score: 70.1552
Created: 14-Jul-2016
Updated: 25-Oct-2021
Structure
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Program:
Drawing:
Aligned Rows:
 
Conserved site includes 14 residues -Click on image for an interactive view with Cn3D
Feature 1:FAD binding site [chemical binding site]
Evidence:
  • Structure:2AF6: Mycobacterium tuberculosis flavin-dependent thymidylate synthase (MtbThyX) tetramer binds 4 FAD molecules; contacts at 4.0A
    View structure with Cn3D
  • Structure:4KAR: Thermotoga maritima flavin-dependent thymidylate synthase binds FAD which interacts with 2 other protein molecules; contacts at 4.0A
    View structure with Cn3D
  • Comment:each FAD molecule makes contacts with 3 of the 4 protein molecules in the tetramer.

Sequence Alignment
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Format: Row Display: Color Bits: Type Selection:
Feature 1                                                                                    #
4FZB_J      9 KLISVTKPVvegvn-------taeeLIAYAARVsnpen-----qinnkTASGLLKYcir----------------hkHWS 60  Paramecium bursari...
2AF6_A     10 QLIAKTDFLappdvpwttdadggpaLVEFAGRAcyqswsk--pnpktaTNAGYLRHixd----------------vgHFS 71  Mycobacterium tube...
OGW16256  302 KLIDFKKNNe--------------aVIAGSVREilgipssksvdkrrlSNERAIRLvldpscnrlygevlnlttmskLTR 367 Nitrospirae bacter...
EKD64245  264 KLISYDKNAe--------------eVVAESVRIatg---------takSTDEIIEEilnpqknpy---lldtlnnwaHSP 317 uncultured bacterium
OGQ13509  283 KLVDQSENAe--------------aTLAQAVRNlfskt------kaemTDEAAIDLvlhpkqnpmlgdtfnvstlskLTR 342 Deltaproteobacteri...
OQY27735  280 KLVDWKIRQes-------------vLASSIREVmglpks----aisdhFAIELVMNpgknplfge---slnmtmhdkLTR 339 Candidatus Cloacim...
PCJ21386  274 KLVDYKINGe--------------qTLARSIRQvfais------kknyTDKELIEWllnpstnki---lsetmninlHSK 330 Candidatus Cloacim...
KKT58230  230 RLIDKYAAKdykavl----lyqpwlIYAITAET---------------IREAVCNRne------------------aELA 272 Candidatus Giovann...
PZN67716  318 KLVAYNPNAe--------------rLLANAVRTvlgrs------rdelSDAEAIALvldparnhy---hghslflamHSK 374 Sphaerobacter ther...
OGM62889  297 RLIGNAANVr--------------lTLADSARGvlgvs------swssNNTKTLDFlmnpkknpyladvyeigmfdpLTS 356 Candidatus Woeseba...
Feature 1       #                       ###                         ## #                      
4FZB_J     61 IFETa---FMTLELKTSr-gIAAQVLRHRs---------------------fHFQEFSQRYasvmetppphqarfqdhkn 115 Paramecium bursari...
2AF6_A     72 VLEHa---SVSFYITGIsrsCTHELIRHRh---------------------fSYSQLSQRYvpekdsrvvvp-------- 119 Mycobacterium tube...
OGW16256  368 ALSHa---SYTFRKKISh-tADSQDQRHRmtpasrpclh---rhitdepdyiTPGLISQNKkv----------------- 423 Nitrospirae bacter...
EKD64245  318 VMRSlnnvNYVFKKRLSh-tADSQDQRHRmtpacrpllsk-vhtsrpdyytpSVIEKNSEVs------------------ 377 uncultured bacterium
OGQ13509  343 ALFHv---HFSFQKKISh-tADSQDQRHRmt-------------------pgSRPILALHYfgepdviypk--------- 390 Deltaproteobacteri...
OQY27735  340 TLNHv---SYSFRRKLSh-tADSQDQRHRttpas-------------rpilhRHISEGPDYitpplie------------ 390 Candidatus Cloacim...
PCJ21386  331 AMRSlmhvHYTFQKKLSh-aADSQDQRHRmtpas-------------rplleSVVSDEADYitpilfe------------ 384 Candidatus Cloacim...
KKT58230  273 NLKHl---HFEFLAKMSl-aCFHQATRQRtwnqsvesiysaaqadfdepysrMFVPVSIERsd----------------- 331 Candidatus Giovann...
PZN67716  375 LMQTmnhvPFTFQKRISg-aEEAQNQRHRgt-------------------lsSSPVLSAHLrqepdvivpy--------- 425 Sphaerobacter ther...
OGM62889  357 VLRQa---SFTFATKLSh-tADSQRQRHRrtpgatpp--------ifasydgSFDYITPMViegn--------------- 409 Candidatus Woeseba...
Feature 1                                                                                # #  
4FZB_J    116 rqnsldtvpeddqtwwaTEQEKLYAQSMELYNKalek---------------giakECARFILPlstPTTIYMSGTiRDW 180 Paramecium bursari...
2AF6_A    120 -------pgxeddadlrHILTEAADAARATYSEllakleakfadqpnailrrkqarQAARAVXPnatETRIVVTGNyRAW 192 Mycobacterium tube...
OGW16256  424 ----------------eKFYKETMDRTWESINKiisl---------------gvseEFAMYLLPnavAIRFTESGDlLNL 472 Nitrospirae bacter...
EKD64245  378 -----------------ALYKETMDMLWEAKNNliem---------------gvpaGDACYLLPnavNVRFIQNGSfLNF 425 uncultured bacterium
OGQ13509  391 --------vflevpkakALFEDVLSQTVQNVNTllka---------------gegfEKAHYLLPnawAIRFIESGDlLNW 447 Deltaproteobacteri...
OQY27735  391 -----------qnpkalRLYQETMEKTWDSINRlrem---------------gtreEFALYLLPnavSVRYTQSADlLSL 444 Candidatus Cloacim...
PCJ21386  385 -----------ldqdlkNTYTNHMQTIWSFYKKakql---------------gmsfENRSYLLPnalTLRFYESSDlLAL 438 Candidatus Cloacim...
KKT58230  332 ---------------ffDRYREMYLKMMALYAKlkqr---------------gipaQEAIGVVPhslMVYDWIHVNgWNA 381 Candidatus Giovann...
PZN67716  426 --------dvarvpealEEYHATVRALWDAKNRllda---------------gvpvEQVLYLLPnshHVRFYETGTlLTY 482 Sphaerobacter ther...
OGM62889  410 -------------aqlnERYDLIMRENYEAVERarem---------------gipdEWALRLLPnahALRVVESGDlFDW 461 Candidatus Woeseba...
Feature 1      #   ##   #                  
4FZB_J    181 IHYIELRtsnGTQREHIDLANACKEIFIK 209 Paramecium bursaria Chlorella virus 1
2AF6_A    193 RHFIAXRaseHADVEIRRLAIECLRQLAA 221 Mycobacterium tuberculosis
OGW16256  473 RHKYAMRlcyNAQEEIWRASLDEVSQIRE 501 Nitrospirae bacterium GWA2_42_11
EKD64245  426 LHKWRLRlcfNAQLEIYEASRDELDAVTA 454 uncultured bacterium
OGQ13509  448 HHKWKLRtcyNAQEEIFYASVAELLEVEK 476 Deltaproteobacteria bacterium RIFCSPHIGHO2_02_FULL_40_11
OQY27735  445 RHKYAMRicyNAQEEIWRLSLEEIRQIRE 473 Candidatus Cloacimonetes bacterium 4572_55
PCJ21386  439 KHKMEMRlcyNAQEEIFFASVDEAKEVYK 467 Candidatus Cloacimonetes bacterium
KKT58230  382 IHAIGKRtceKAQLEIRRIAWAMANQIKT 410 Candidatus Giovannonibacteria bacterium GW2011_GWA1_44_25
PZN67716  483 FWKWVKRlcyDAQREIFETARQETEQVKQ 511 Sphaerobacter thermophilus
OGM62889  462 LHRLKQRlcyLAQEEIFFISVDQAEQLTG 490 Candidatus Woesebacteria bacterium RIFCSPLOWO2_01_FULL_39_21

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