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 410811823   3 LGCSPEERYFKQPILVSVVLSFFKEPSVyVSDDLVDACCYVEITSLIEEVASSKPCALVEHLSKILMDALEAKlKDKVSK 82
Cdd:cd00534   15 HGVFEEERLLGQKFVVDLTLWYDLSKAG-ESDDLADTLNYAEVAKLIKKIVEGSPFKLIETLAEEIADILLED-YPKVSA 92

                         90       100
                 ....*....|....*....|....*.
gi 410811823  83 IDLEVRKERPPVPNLLKPICFKIIRE 108
Cdd:cd00534   93 IKVKVEKPNAPIPASADGVGVEIERE 118

Dihydroneopterin aldolase (DHNA) and 7,8-dihydroneopterin triphosphate epimerase domain (DHNTPE); these enzymes have been designated folB and folX, respectively. Folate derivatives are essential cofactors in the biosynthesis of purines, pyrimidines, and amino acids, as well as formyl-tRNA. Mammalian cells are able to utilize pre-formed folates after uptake by a carrier-mediated active transport system. Most microbes and plants lack this system and must synthesize folates de novo from guanosine triphosphate. One enzyme from this pathway is DHNA which catalyses the conversion of 7,8-dihydroneopterin to 6-hydroxymethyl-7,8-dihydropterin in the biosynthetic pathway of tetrahydrofolate. Though it is known that DHNTPE catalyzes the epimerization of dihydroneopterin triphosphate to dihydromonapterin triphosphate, the biological role of this enzyme is still unclear. It is hypothesized that it is not an essential protein since a folX knockout in E. coli has a normal phenotype and the fact that folX is not present in H. influenza. In addition both enzymes have been shown to be able to compensate for the other's activity albeit at slower reaction rates. The functional enzyme for both is an octamer of identical subunits. Mammals lack many of the enzymes in the folate pathway including, DHNA and DHNTPE.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 410811823   3 LGCSPEERYFKQPILVSVVLSFFKEPSVyVSDDLVDACCYVEITSLIEEVASSKPCALVEHLSKILMDALEAKlKDKVSK 82
Cdd:cd00534   15 HGVFEEERLLGQKFVVDLTLWYDLSKAG-ESDDLADTLNYAEVAKLIKKIVEGSPFKLIETLAEEIADILLED-YPKVSA 92

                         90       100
                 ....*....|....*....|....*.
gi 410811823  83 IDLEVRKERPPVPNLLKPICFKIIRE 108
Cdd:cd00534   93 IKVKVEKPNAPIPASADGVGVEIERE 118

Dihydroneopterin aldolase; Dihydroneopterin aldolase catalyses the conversion of 7,8-dihydroneopterin to 6-hydroxymethyl-7,8-dihydropterin in the biosynthetic pathway of tetrahydrofolate. In the opportunistic pathogen Pneumocystis carinii, dihydroneopterin aldolase function is expressed as the N-terminal portion of the multifunctional folic acid synthesis protein (Fas). This region encompasses two domains, FasA and FasB, which are 27% amino acid identical. FasA and FasB also share significant amino acid sequence similarity with bacterial dihydroneopterin aldolases. This region consists of two tandem sequences each homologous to folB and which form tetramers.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 410811823     2 HLGCSPEERYFKQPILVSVVLSFFKEPSVYVSDDLVDACCYVEITSLIEEVASSKPCALVEHLSKILMDALEAklKDKVS 81
Cdd:smart00905  11 YIGVLDWERELGQRFVVDLELAWDDLRKAAESDDLEDTVDYAEVSERIKELVEGSRFKLIETLAERIADLLLE--DFGVE 88

                           90
                   ....*....|....*
gi 410811823    82 KIDLEVRKERPPVPN 96
Cdd:smart00905  89 AVRVKVTKPNAPIPG 103

Dihydroneopterin aldolase; This enzyme EC:4.1.2.25 catalyzes the conversion of 7,8-dihydroneopterin to 6-hydroxymethyl-7,8-dihydropterin in the biosynthetic pathway of tetrahydrofolate.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 410811823    2 HLGCSPEERYFKQPILVSVVLSF-FKEPSVyvSDDLVDACCYVEITSLIEEVASSKPCALVEHLSKILMDALEAKLKdKV 80
Cdd:pfam02152  11 YHGVYPEERRLGQRFVVDLELWLdLSKAAA--TDDLEDTVDYAEVYEAVKELVEGEPFKLLETLAERIADRLLEEFP-GV 87

                          90
                  ....*....|....*
gi 410811823   81 SKIDLEVRKERPPVP 95
Cdd:pfam02152  88 EAVRVRVEKPNAPIP 102

Dihydroneopterin aldolase (DHNA) and 7,8-dihydroneopterin triphosphate epimerase domain (DHNTPE); these enzymes have been designated folB and folX, respectively. Folate derivatives are essential cofactors in the biosynthesis of purines, pyrimidines, and amino acids, as well as formyl-tRNA. Mammalian cells are able to utilize pre-formed folates after uptake by a carrier-mediated active transport system. Most microbes and plants lack this system and must synthesize folates de novo from guanosine triphosphate. One enzyme from this pathway is DHNA which catalyses the conversion of 7,8-dihydroneopterin to 6-hydroxymethyl-7,8-dihydropterin in the biosynthetic pathway of tetrahydrofolate. Though it is known that DHNTPE catalyzes the epimerization of dihydroneopterin triphosphate to dihydromonapterin triphosphate, the biological role of this enzyme is still unclear. It is hypothesized that it is not an essential protein since a folX knockout in E. coli has a normal phenotype and the fact that folX is not present in H. influenza. In addition both enzymes have been shown to be able to compensate for the other's activity albeit at slower reaction rates. The functional enzyme for both is an octamer of identical subunits. Mammals lack many of the enzymes in the folate pathway including, DHNA and DHNTPE.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 410811823   3 LGCSPEERYFKQPILVSVVLSFFKEPSVyVSDDLVDACCYVEITSLIEEVASSKPCALVEHLSKILMDALEAKlKDKVSK 82
Cdd:cd00534   15 HGVFEEERLLGQKFVVDLTLWYDLSKAG-ESDDLADTLNYAEVAKLIKKIVEGSPFKLIETLAEEIADILLED-YPKVSA 92

                         90       100
                 ....*....|....*....|....*.
gi 410811823  83 IDLEVRKERPPVPNLLKPICFKIIRE 108
Cdd:cd00534   93 IKVKVEKPNAPIPASADGVGVEIERE 118

Dihydroneopterin aldolase; Dihydroneopterin aldolase catalyses the conversion of 7,8-dihydroneopterin to 6-hydroxymethyl-7,8-dihydropterin in the biosynthetic pathway of tetrahydrofolate. In the opportunistic pathogen Pneumocystis carinii, dihydroneopterin aldolase function is expressed as the N-terminal portion of the multifunctional folic acid synthesis protein (Fas). This region encompasses two domains, FasA and FasB, which are 27% amino acid identical. FasA and FasB also share significant amino acid sequence similarity with bacterial dihydroneopterin aldolases. This region consists of two tandem sequences each homologous to folB and which form tetramers.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 410811823     2 HLGCSPEERYFKQPILVSVVLSFFKEPSVYVSDDLVDACCYVEITSLIEEVASSKPCALVEHLSKILMDALEAklKDKVS 81
Cdd:smart00905  11 YIGVLDWERELGQRFVVDLELAWDDLRKAAESDDLEDTVDYAEVSERIKELVEGSRFKLIETLAERIADLLLE--DFGVE 88

                           90
                   ....*....|....*
gi 410811823    82 KIDLEVRKERPPVPN 96
Cdd:smart00905  89 AVRVKVTKPNAPIPG 103

Dihydroneopterin aldolase [Coenzyme transport and metabolism]; Dihydroneopterin aldolase is part of the Pathway/BioSystem: Folate biosynthesis

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 410811823   2 HLGCSPEERYFKQPILVSVVLSFFKEPSVyVSDDLVDACCYVEITSLIEEVASSKPCALVEHLSKILMDALEAKLkDKVS 81
Cdd:COG1539   14 YHGVYDEERELGQRFVVDLELELDLRKAA-ASDDLADTVDYAEVAEAIKELVEGEHFNLIETLAERIADRLLAEF-PRVE 91

                         90
                 ....*....|....
gi 410811823  82 KIDLEVRKERPPVP 95
Cdd:COG1539   92 AVRVRVRKPDAPIG 105

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 410811823   3 LGCSPEERYFKQPILVSVVLSFFKEPSVyVSDDLVDACCYVEITSLIEEVASSKpcALVEHLSKILMDALEAKLKDKVSK 82
Cdd:cd00651   15 LGFVTLERTVGQIFEVDVTLSWDGKKAA-ASDDVATDTVYNTIYRLAKEYVEGS--QLIERLAEEIAYLIAEHFLSSVAE 91

                         90
                 ....*....|...
gi 410811823  83 IDLEVRKERPPVP 95
Cdd:cd00651   92 VKVEEKKPHAVIP 104