Tunnelling fold (T-fold). The five known T-folds are found in five different enzymes with different functions: dihydroneopterin-triphosphate epimerase (DHNTPE), dihydroneopterin aldolase (DHNA) , GTP cyclohydrolase I (GTPCH-1), 6-pyrovoyl tetrahydropterin synthetase (PTPS), and uricase (UO,uroate/urate oxidase). They bind to substrates belonging to the purine or pterin families, and share a fold-related binding site with a glutamate or glutamine residue anchoring the substrate and a lot of conserved interactions. They also share a similar oligomerization mode: several T-folds join together to form a beta(2n)alpha(n) barrel, then two barrels join together in a head-to-head fashion to made up the native enzymes. The functional enzyme is a tetramer for UO, a hexamer for PTPS, an octamer for DHNA/DHNTPE and a decamer for GTPCH-1. The substrate is located in a deep and narrow pocket at the interface between monomers. In PTPS, the active site is located at the interface of three monomers, two from one trimer and one from the other trimer. In GTPCH-1, it is also located at the interface of three subunits, two from one pentamer and one from the other pentamer. There are four equivalent active sites in UO, six in PTPS, eight in DHNA/DHNTPE and ten in GTPCH-1. Each globular multimeric enzyme encloses a tunnel which is lined with charged residues for DHNA and UO, and with basic residues in PTPS. The N and C-terminal ends are located on one side of the T-fold while the residues involved in the catalytic activity are located at the opposite side. In PTPS, UO and DHNA/DHNTPE, the N and C-terminal extremities of the enzyme are located on the exterior side of the functional multimeric enzyme. In GTPCH-1, the extra C-terminal helix places the extremity inside the tunnel.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217297132  66 LNLPNLAAAYSSILSSLGENPQRQGLLKTPWRAASAMQFFTKGYQETISDVLNDAIFDEDHDEMVIVKDIDMFSMCEHHL 145
Cdd:cd00642     1 ERLEKIAAAVREILELLGEDPNREGLLETPERVAKAYQEITSGYDQALNDPKNTAIFDEDHDEMVIVKDITLFSMCEHHL 80

                          90       100
                  ....*....|....*....|....*
gi 2217297132 146 VPFVGKVHIGYLPNKQVLGLSKLAR 170
Cdd:cd00642    81 VPFYGKVHIAYIPKDKVIGLSKLAR 105

GTP cyclohydrolase I (GTP-CH-I) catalyzes the conversion of GTP into dihydroneopterin triphosphate. The enzyme product is the precursor of tetrahydrofolate in eubacteria, fungi, and plants and of the folate analogs in methanogenic bacteria. In vertebrates and insects it is the biosynthtic precursor of tetrahydrobiopterin (BH4) which is involved in the formation of catacholamines, nitric oxide, and the stimulation of T lymphocytes. The biosynthetic reaction of BH4 is controlled by a regulatory protein GFRP which mediates feedback inhibition of GTP-CH-I by BH4. This inhibition is reversed by phenylalanine. The decameric GTP-CH-I forms a complex with two pentameric GFRP in the presence of phenylalanine or a combination of GTP and BH4, respectively.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217297132  66 LNLPNLAAAYSSILSSLGENPQRQGLLKTPWRAASAMQFFTKGYQETISDVLNDAIFDEDHDEMVIVKDIDMFSMCEHHL 145
Cdd:cd00642     1 ERLEKIAAAVREILELLGEDPNREGLLETPERVAKAYQEITSGYDQALNDPKNTAIFDEDHDEMVIVKDITLFSMCEHHL 80

                          90       100
                  ....*....|....*....|....*
gi 2217297132 146 VPFVGKVHIGYLPNKQVLGLSKLAR 170
Cdd:cd00642    81 VPFYGKVHIAYIPKDKVIGLSKLAR 105

GTP cyclohydrolase I; This family includes GTP cyclohydrolase enzymes and a family of related bacterial proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217297132  71 LAAAYSSILSSLGENPQRQGLLKTPWRAASAMQFFTKGYQETISDVLNdAIFDEDHDEMVIVKDIDMFSMCEHHLVPFVG 150
Cdd:pfam01227   1 IEEAVREILEAIGEDPDREGLLETPKRVAKMYEELFSGYHEDPEKVLK-ATFEEGYDEMVLVKDIEFYSMCEHHLLPFFG 79

                          90       100
                  ....*....|....*....|
gi 2217297132 151 KVHIGYLPNKQVLGLSKLAR 170
Cdd:pfam01227  80 KAHVAYIPNGKVIGLSKIAR 99

GTP cyclohydrolase I; alternate names: Punch (Drosophila),GTP cyclohydrolase I (EC 3.5.4.16) catalyzes the biosynthesis of formic acid and dihydroneopterin triphosphate from GTP. This reaction is the first step in the biosynthesis of tetrahydrofolate in prokaryotes, of tetrahydrobiopterin in vertebrates, and of pteridine-containing pigments in insects. [Biosynthesis of cofactors, prosthetic groups, and carriers, Folic acid]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217297132  71 LAAAYSSILSSLGENPQRQGLLKTPWRAASAMQFFTKGYQETISDVLNDAIFDEDHDEMVIVKDIDMFSMCEHHLVPFVG 150
Cdd:TIGR00063   1 IAGAMREILELIGEDLNREGLLETPKRVAKMYVEIFSGYDYANFPKITLAIFQEKHDEMVLVRDITFTSTCEHHLVPFDG 80

                          90       100
                  ....*....|....*....|
gi 2217297132 151 KVHIGYLPNKQVLGLSKLAR 170
Cdd:TIGR00063  81 KAHVAYIPKDKVIGLSKIAR 100

GTP cyclohydrolase I (GTP-CH-I) catalyzes the conversion of GTP into dihydroneopterin triphosphate. The enzyme product is the precursor of tetrahydrofolate in eubacteria, fungi, and plants and of the folate analogs in methanogenic bacteria. In vertebrates and insects it is the biosynthtic precursor of tetrahydrobiopterin (BH4) which is involved in the formation of catacholamines, nitric oxide, and the stimulation of T lymphocytes. The biosynthetic reaction of BH4 is controlled by a regulatory protein GFRP which mediates feedback inhibition of GTP-CH-I by BH4. This inhibition is reversed by phenylalanine. The decameric GTP-CH-I forms a complex with two pentameric GFRP in the presence of phenylalanine or a combination of GTP and BH4, respectively.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217297132  66 LNLPNLAAAYSSILSSLGENPQRQGLLKTPWRAASAMQFFTKGYQETISDVLNDAIFDEDHDEMVIVKDIDMFSMCEHHL 145
Cdd:cd00642     1 ERLEKIAAAVREILELLGEDPNREGLLETPERVAKAYQEITSGYDQALNDPKNTAIFDEDHDEMVIVKDITLFSMCEHHL 80

                          90       100
                  ....*....|....*....|....*
gi 2217297132 146 VPFVGKVHIGYLPNKQVLGLSKLAR 170
Cdd:cd00642    81 VPFYGKVHIAYIPKDKVIGLSKLAR 105

GTP cyclohydrolase I; This family includes GTP cyclohydrolase enzymes and a family of related bacterial proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217297132  71 LAAAYSSILSSLGENPQRQGLLKTPWRAASAMQFFTKGYQETISDVLNdAIFDEDHDEMVIVKDIDMFSMCEHHLVPFVG 150
Cdd:pfam01227   1 IEEAVREILEAIGEDPDREGLLETPKRVAKMYEELFSGYHEDPEKVLK-ATFEEGYDEMVLVKDIEFYSMCEHHLLPFFG 79

                          90       100
                  ....*....|....*....|
gi 2217297132 151 KVHIGYLPNKQVLGLSKLAR 170
Cdd:pfam01227  80 KAHVAYIPNGKVIGLSKIAR 99

GTP cyclohydrolase I; Reviewed

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217297132  66 LNLPNLAAAYSSILSSLGENPQRQGLLKTPWRAASAMQFFTKGYQETISDVLNdAIFDEDHDEMVIVKDIDMFSMCEHHL 145
Cdd:PRK12606   17 FDPPALEAAVRELLEALGEDPDREGLLDTPQRVAKAMQYLCDGYEQDPAEALG-ALFDSDNDEMVIVRDIELYSLCEHHL 95

                          90       100
                  ....*....|....*....|....*
gi 2217297132 146 VPFVGKVHIGYLPNKQVLGLSKLAR 170
Cdd:PRK12606   96 LPFIGVAHVAYLPGGKVLGLSKIAR 120

GTP cyclohydrolase I; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217297132  10 AEKPRGARCSNGfpeRD-PPRPGPSRPAEKPPRPEAKSAQPADGWKGERPR-SEEDNELNLPNLAAAYSSILSSL-GENP 86
Cdd:PTZ00484   16 GNEENGDISRNC---RDgDIDNDANLSLLDEDASLGKGRQSNSGPSTESSPtCATLMEEKKGAIESARRKILKSLeGEDP 92

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217297132  87 QRQGLLKTPWRAASAMQFFTKGYQETISDVLNDAIFD---EDHDEMVIVKDIDMFSMCEHHLVPFVGKVHIGYLPNKQVL 163
Cdd:PTZ00484   93 DRDGLKKTPKRVAKALEFLTKGYHMSVEEVIKKALFKvepKNNDEMVKVRDIDIFSLCEHHLLPFEGECTIGYIPNKKVL 172

                  ....*..
gi 2217297132 164 GLSKLAR 170
Cdd:PTZ00484  173 GLSKFAR 179

GTP cyclohydrolase I

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217297132  71 LAAAYSSILSSLGENPQRQGLLKTPWRAASAMQFFTKGYQETISDVLNDAIFDE---DHDE--------MVIVKDIDMFS 139
Cdd:PLN02531   35 IESAVKVLLQGLGEDVNREGLKKTPLRVAKALREATRGYKQSAKDIVGGALFPEaglDDGVghgggcggLVVVRDLDLFS 114

                          90       100       110
                  ....*....|....*....|....*....|..
gi 2217297132 140 MCEHHLVPFVGKVHIGYLPNKQ-VLGLSKLAR 170
Cdd:PLN02531  115 YCESCLLPFQVKCHIGYVPSGQrVVGLSKLSR 146

Tunnelling fold (T-fold). The five known T-folds are found in five different enzymes with different functions: dihydroneopterin-triphosphate epimerase (DHNTPE), dihydroneopterin aldolase (DHNA) , GTP cyclohydrolase I (GTPCH-1), 6-pyrovoyl tetrahydropterin synthetase (PTPS), and uricase (UO,uroate/urate oxidase). They bind to substrates belonging to the purine or pterin families, and share a fold-related binding site with a glutamate or glutamine residue anchoring the substrate and a lot of conserved interactions. They also share a similar oligomerization mode: several T-folds join together to form a beta(2n)alpha(n) barrel, then two barrels join together in a head-to-head fashion to made up the native enzymes. The functional enzyme is a tetramer for UO, a hexamer for PTPS, an octamer for DHNA/DHNTPE and a decamer for GTPCH-1. The substrate is located in a deep and narrow pocket at the interface between monomers. In PTPS, the active site is located at the interface of three monomers, two from one trimer and one from the other trimer. In GTPCH-1, it is also located at the interface of three subunits, two from one pentamer and one from the other pentamer. There are four equivalent active sites in UO, six in PTPS, eight in DHNA/DHNTPE and ten in GTPCH-1. Each globular multimeric enzyme encloses a tunnel which is lined with charged residues for DHNA and UO, and with basic residues in PTPS. The N and C-terminal ends are located on one side of the T-fold while the residues involved in the catalytic activity are located at the opposite side. In PTPS, UO and DHNA/DHNTPE, the N and C-terminal extremities of the enzyme are located on the exterior side of the functional multimeric enzyme. In GTPCH-1, the extra C-terminal helix places the extremity inside the tunnel.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 2217297132 127 DEMVIVKDIDMFSMC----EHHLVPFVGKVHIGYLPNKQVLGLS 166
Cdd:cd00651     1 TDGVRVKDLLKVTRLgfvtLERTVGQIFEVDVTLSWDGKKAAAS 44