dihydroneopterin triphosphate 2'-epimerase;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1352181490   1 MAQPAAIIRIKNLRLRTFIGIKEEEINNRQDIVINVTIHYPADKARTSEDINDALNYRTVTKNIIQHVENNRFSLLEKLT 80
Cdd:PRK11245    1 MAPPAAIIRIKNLRLRTFIGIKEEEINNRQDVVINVTIHYPADKARTSDDIDDALNYRTITKNIIQHVENNRFSLLEKLT 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1352181490  81 QDVLDIAREHHWVTYAEVEIDKLHALRYADSVSMTLSWQR 120
Cdd:PRK11245   81 QDVLDIAREHPWVTYAEVEIDKPHALRFADSVSMTLSWQR 120

dihydroneopterin triphosphate 2'-epimerase;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1352181490   1 MAQPAAIIRIKNLRLRTFIGIKEEEINNRQDIVINVTIHYPADKARTSEDINDALNYRTVTKNIIQHVENNRFSLLEKLT 80
Cdd:PRK11245    1 MAPPAAIIRIKNLRLRTFIGIKEEEINNRQDVVINVTIHYPADKARTSDDIDDALNYRTITKNIIQHVENNRFSLLEKLT 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1352181490  81 QDVLDIAREHHWVTYAEVEIDKLHALRYADSVSMTLSWQR 120
Cdd:PRK11245   81 QDVLDIAREHPWVTYAEVEIDKPHALRFADSVSMTLSWQR 120

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 1352181490   5 AAIIRIKNLRLRTFIGIKEEEINNRQDIVINVTIHYPADKARTSEDINDALNYRTVTKNIIQHVENNRFSLLEKLTQDVL 84
Cdd:cd00534     1 MDRVFIKGLRFYTIHGVFEEERLLGQKFVVDLTLWYDLSKAGESDDLADTLNYAEVAKLIKKIVEGSPFKLIETLAEEIA 80

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1352181490  85 DIAREH-HWVTYAEVEIDKLHAL--RYADSVSMTLSWQ 119
Cdd:cd00534    81 DILLEDyPKVSAIKVKVEKPNAPipASADGVGVEIERE 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 1352181490    8 IRIKNLRLRTFIGIKEEEINNRQDIVINVTIHYP-ADKARTSEDINDALNYRTVTKNIIQHVENNRFSLLEKLTQDVLDI 86
Cdd:smart00905   1 IFIKGLRFYAYIGVLDWERELGQRFVVDLELAWDdLRKAAESDDLEDTVDYAEVSERIKELVEGSRFKLIETLAERIADL 80

                           90       100       110
                   ....*....|....*....|....*....|...
gi 1352181490   87 AREHHWVTYAEVEIDKLHALRYADS-VSMTLSW 118
Cdd:smart00905  81 LLEDFGVEAVRVKVTKPNAPIPGDSdVGVEIER 113

dihydroneopterin triphosphate 2'-epimerase;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1352181490   1 MAQPAAIIRIKNLRLRTFIGIKEEEINNRQDIVINVTIHYPADKARTSEDINDALNYRTVTKNIIQHVENNRFSLLEKLT 80
Cdd:PRK11245    1 MAPPAAIIRIKNLRLRTFIGIKEEEINNRQDVVINVTIHYPADKARTSDDIDDALNYRTITKNIIQHVENNRFSLLEKLT 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1352181490  81 QDVLDIAREHHWVTYAEVEIDKLHALRYADSVSMTLSWQR 120
Cdd:PRK11245   81 QDVLDIAREHPWVTYAEVEIDKPHALRFADSVSMTLSWQR 120

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 1352181490   5 AAIIRIKNLRLRTFIGIKEEEINNRQDIVINVTIHYPADKARTSEDINDALNYRTVTKNIIQHVENNRFSLLEKLTQDVL 84
Cdd:cd00534     1 MDRVFIKGLRFYTIHGVFEEERLLGQKFVVDLTLWYDLSKAGESDDLADTLNYAEVAKLIKKIVEGSPFKLIETLAEEIA 80

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1352181490  85 DIAREH-HWVTYAEVEIDKLHAL--RYADSVSMTLSWQ 119
Cdd:cd00534    81 DILLEDyPKVSAIKVKVEKPNAPipASADGVGVEIERE 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 1352181490    8 IRIKNLRLRTFIGIKEEEINNRQDIVINVTIHYP-ADKARTSEDINDALNYRTVTKNIIQHVENNRFSLLEKLTQDVLDI 86
Cdd:smart00905   1 IFIKGLRFYAYIGVLDWERELGQRFVVDLELAWDdLRKAAESDDLEDTVDYAEVSERIKELVEGSRFKLIETLAERIADL 80

                           90       100       110
                   ....*....|....*....|....*....|...
gi 1352181490   87 AREHHWVTYAEVEIDKLHALRYADS-VSMTLSW 118
Cdd:smart00905  81 LLEDFGVEAVRVKVTKPNAPIPGDSdVGVEIER 113

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 1352181490   8 IRIKNLRLRTFIGIKEEEINNRQDIVINVTIHYPADKARTSEDINDALNYRTVTKNIIQHVENNRfsLLEKLTQDVLDIA 87
Cdd:cd00651     4 VRVKDLLKVTRLGFVTLERTVGQIFEVDVTLSWDGKKAAASDDVATDTVYNTIYRLAKEYVEGSQ--LIERLAEEIAYLI 81

                          90       100
                  ....*....|....*....|
gi 1352181490  88 REHHW--VTYAEVEIDKLHA 105
Cdd:cd00651    82 AEHFLssVAEVKVEEKKPHA 101

dihydroneopterin aldolase; This model describes a bacterial dihydroneopterin aldolase, shown to form homo-octamers in E. coli. The equivalent activity is catalyzed by domains of larger folate biosynthesis proteins in other systems. The closely related parologous enzyme in E. coli, dihydroneopterin triphosphate epimerase, which is also homo-octameric, and dihydroneopterin aldolase domains of larger proteins, score below the trusted cutoff but may score well above the noise cutoff. [Biosynthesis of cofactors, prosthetic groups, and carriers, Folic acid]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1352181490   8 IRIKNLRLRTFIGIKEEEINNRQDIVINVTIHYPADKARTSEDINDALNYRTVTKNIIQHVENNRFSLLEKLTQDVLD-I 86
Cdd:TIGR00525   3 VFIEGLEVFAYHGVFDHERVLGQRFVVDLELSVDETKAAESDDLGDTVNYAELYSAIEEIVAEKPRDLIETVAYRIADrL 82

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1352181490  87 AREHHWVTYAEVEIDKLHAL--RYADSVSMTLS 117
Cdd:TIGR00525  83 FADFPQVQRVKVRVSKPNAPipGHLDDVSVEIR 115