FOL1_PNECA
ID FOL1_PNECA Reviewed; 740 AA.
AC P29251;
DT 01-DEC-1992, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-1992, sequence version 1.
DT 03-AUG-2022, entry version 106.
DE RecName: Full=Folic acid synthesis protein fol1;
DE Includes:
DE RecName: Full=Dihydroneopterin aldolase {ECO:0000303|PubMed:8397083};
DE Short=DHNA {ECO:0000303|PubMed:7543066};
DE EC=4.1.2.25 {ECO:0000269|PubMed:7950384, ECO:0000269|PubMed:8397083};
DE AltName: Full=7,8-dihydroneopterin aldolase;
DE AltName: Full=FasA {ECO:0000303|PubMed:8397083};
DE AltName: Full=FasB {ECO:0000303|PubMed:8397083};
DE Includes:
DE RecName: Full=6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase {ECO:0000303|PubMed:8397083};
DE Short=HPPK;
DE EC=2.7.6.3 {ECO:0000269|PubMed:7950384, ECO:0000269|PubMed:8397083};
DE AltName: Full=2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase;
DE AltName: Full=7,8-dihydro-6-hydroxymethylpterin-pyrophosphokinase;
DE Short=PPPK {ECO:0000303|PubMed:7950384};
DE AltName: Full=Dihydropterin pyrophosphokinase {ECO:0000303|PubMed:8397083};
DE AltName: Full=FasC {ECO:0000303|PubMed:8397083};
DE Includes:
DE RecName: Full=Dihydropteroate synthase {ECO:0000303|PubMed:8397083};
DE Short=DHPS {ECO:0000303|PubMed:7950384};
DE EC=2.5.1.15 {ECO:0000269|PubMed:8397083};
DE AltName: Full=Dihydropteroate pyrophosphorylase;
DE AltName: Full=FasD {ECO:0000303|PubMed:8397083};
GN Name=fol1; Synonyms=fas {ECO:0000303|PubMed:8397083};
OS Pneumocystis carinii.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Taphrinomycotina;
OC Pneumocystidomycetes; Pneumocystidaceae; Pneumocystis.
OX NCBI_TaxID=4754;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=1313386; DOI=10.1016/0378-1119(92)90378-3;
RA Volpes F., Dyer M., Scaife J.G., Darby G., Stammers D.K., Delves C.J.;
RT "The multifunctional folic acid synthesis fas gene of Pneumocystis carinii
RT appears to encode dihydropteroate synthase and hydroxymethyldihydropterin
RT pyrophosphokinase.";
RL Gene 112:213-218(1992).
RN [2]
RP PROTEIN SEQUENCE OF 1-20, FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=8397083; DOI=10.1111/j.1432-1033.1993.tb18163.x;
RA Volpe F., Ballantine S.P., Delves C.J.;
RT "The multifunctional folic acid synthesis fas gene of Pneumocystis carinii
RT encodes dihydroneopterin aldolase, hydroxymethyldihydropterin
RT pyrophosphokinase and dihydropteroate synthase.";
RL Eur. J. Biochem. 216:449-458(1993).
RN [3]
RP PROTEIN SEQUENCE OF 281-293, BIOPHYSICOCHEMICAL PROPERTIES, AND CATALYTIC
RP ACTIVITY.
RX PubMed=7950384; DOI=10.1006/prep.1994.1054;
RA Ballantine S.P., Volpe F., Delves C.J.;
RT "The hydroxymethyldihydropterin pyrophosphokinase domain of the
RT multifunctional folic acid synthesis Fas protein of Pneumocystis carinii
RT expressed as an independent enzyme in Escherichia coli: refolding and
RT characterization of the recombinant enzyme.";
RL Protein Expr. Purif. 5:371-378(1994).
RN [4]
RP CATALYTIC ACTIVITY.
RX PubMed=7543066; DOI=10.1016/0378-1119(95)00203-i;
RA Volpe F., Ballantine S.P., Delves C.J.;
RT "Two domains with amino-acid sequence similarity are required for
RT dihydroneopterin aldolase function in the multifunctional folic acid
RT synthesis Fas protein of Pneumocystis carinii.";
RL Gene 160:41-46(1995).
RN [5]
RP BIOPHYSICOCHEMICAL PROPERTIES, AND MUTAGENESIS OF ASP-39; GLY-53; GLN-63;
RP ASP-161; GLY-175 AND GLN-185.
RX PubMed=9709001; DOI=10.1021/bi980540x;
RA Thomas M.C., Ballantine S.P., Bethell S.S., Bains S., Kellam P.,
RA Delves C.J.;
RT "Single amino acid substitutions disrupt tetramer formation in the
RT dihydroneopterin aldolase enzyme of Pneumocystis carinii.";
RL Biochemistry 37:11629-11636(1998).
CC -!- FUNCTION: Catalyzes three sequential steps of tetrahydrofolate
CC biosynthesis. {ECO:0000269|PubMed:8397083}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=7,8-dihydroneopterin = 6-hydroxymethyl-7,8-dihydropterin +
CC glycolaldehyde; Xref=Rhea:RHEA:10540, ChEBI:CHEBI:17001,
CC ChEBI:CHEBI:17071, ChEBI:CHEBI:44841; EC=4.1.2.25;
CC Evidence={ECO:0000269|PubMed:7543066, ECO:0000269|PubMed:7950384,
CC ECO:0000269|PubMed:8397083};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=6-hydroxymethyl-7,8-dihydropterin + ATP = (7,8-dihydropterin-
CC 6-yl)methyl diphosphate + AMP + H(+); Xref=Rhea:RHEA:11412,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:44841,
CC ChEBI:CHEBI:72950, ChEBI:CHEBI:456215; EC=2.7.6.3;
CC Evidence={ECO:0000269|PubMed:7543066, ECO:0000269|PubMed:7950384,
CC ECO:0000269|PubMed:8397083};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(7,8-dihydropterin-6-yl)methyl diphosphate + 4-aminobenzoate =
CC 7,8-dihydropteroate + diphosphate; Xref=Rhea:RHEA:19949,
CC ChEBI:CHEBI:17836, ChEBI:CHEBI:17839, ChEBI:CHEBI:33019,
CC ChEBI:CHEBI:72950; EC=2.5.1.15; Evidence={ECO:0000269|PubMed:7543066,
CC ECO:0000269|PubMed:7950384, ECO:0000269|PubMed:8397083};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:P0AC13};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=2.3 uM for 7,8-dihydroneopterin {ECO:0000269|PubMed:7950384,
CC ECO:0000269|PubMed:9709001};
CC KM=3.6 uM for 6-hydroxymethyl-7,8-dihydropterin
CC {ECO:0000269|PubMed:7950384, ECO:0000269|PubMed:9709001};
CC Vmax=36 nmol/min/mg enzyme for 7,8-dihydroneopterin
CC {ECO:0000269|PubMed:7950384, ECO:0000269|PubMed:9709001};
CC pH dependence:
CC Optimum pH is 8. {ECO:0000269|PubMed:7950384,
CC ECO:0000269|PubMed:9709001};
CC -!- PATHWAY: Cofactor biosynthesis; tetrahydrofolate biosynthesis; 2-amino-
CC 4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate from 7,8-
CC dihydroneopterin triphosphate: step 3/4.
CC -!- PATHWAY: Cofactor biosynthesis; tetrahydrofolate biosynthesis; 2-amino-
CC 4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine diphosphate from 7,8-
CC dihydroneopterin triphosphate: step 4/4.
CC -!- PATHWAY: Cofactor biosynthesis; tetrahydrofolate biosynthesis; 7,8-
CC dihydrofolate from 2-amino-4-hydroxy-6-hydroxymethyl-7,8-
CC dihydropteridine diphosphate and 4-aminobenzoate: step 1/2.
CC -!- SIMILARITY: In the N-terminal section; belongs to the DHNA family.
CC {ECO:0000305}.
CC -!- SIMILARITY: In the central section; belongs to the HPPK family.
CC {ECO:0000305}.
CC -!- SIMILARITY: In the C-terminal section; belongs to the DHPS family.
CC {ECO:0000305}.
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DR EMBL; M86602; AAA33790.1; -; Genomic_DNA.
DR PIR; S28666; S28666.
DR AlphaFoldDB; P29251; -.
DR SMR; P29251; -.
DR SABIO-RK; P29251; -.
DR UniPathway; UPA00077; UER00154.
DR UniPathway; UPA00077; UER00155.
DR UniPathway; UPA00077; UER00156.
DR GO; GO:0003848; F:2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase activity; IEA:UniProtKB-EC.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004150; F:dihydroneopterin aldolase activity; IEA:UniProtKB-EC.
DR GO; GO:0004156; F:dihydropteroate synthase activity; IEA:UniProtKB-EC.
DR GO; GO:0016301; F:kinase activity; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0046656; P:folic acid biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW.
DR GO; GO:0046654; P:tetrahydrofolate biosynthetic process; IEA:UniProtKB-UniPathway.
DR CDD; cd00534; DHNA_DHNTPE; 2.
DR CDD; cd00739; DHPS; 1.
DR CDD; cd00483; HPPK; 1.
DR Gene3D; 3.20.20.20; -; 1.
DR Gene3D; 3.30.1130.10; -; 2.
DR Gene3D; 3.30.70.560; -; 1.
DR InterPro; IPR045031; DHP_synth.
DR InterPro; IPR006390; DHP_synth_dom.
DR InterPro; IPR011005; Dihydropteroate_synth-like.
DR InterPro; IPR006157; FolB_dom.
DR InterPro; IPR016261; Folic_acid_synth.
DR InterPro; IPR043133; GTP-CH-I_C/QueF.
DR InterPro; IPR000550; Hppk.
DR InterPro; IPR035907; Hppk_sf.
DR InterPro; IPR000489; Pterin-binding_dom.
DR PANTHER; PTHR20941; PTHR20941; 1.
DR Pfam; PF02152; FolB; 2.
DR Pfam; PF01288; HPPK; 1.
DR Pfam; PF00809; Pterin_bind; 1.
DR PIRSF; PIRSF000741; Folic_acid_synth; 1.
DR SMART; SM00905; FolB; 2.
DR SUPFAM; SSF51717; SSF51717; 1.
DR SUPFAM; SSF55083; SSF55083; 1.
DR TIGRFAMs; TIGR01496; DHPS; 1.
DR TIGRFAMs; TIGR00526; folB_dom; 2.
DR TIGRFAMs; TIGR01498; folK; 1.
DR PROSITE; PS00792; DHPS_1; 1.
DR PROSITE; PS00793; DHPS_2; 1.
DR PROSITE; PS00794; HPPK; 1.
DR PROSITE; PS50972; PTERIN_BINDING; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Direct protein sequencing; Folate biosynthesis; Kinase; Lyase;
KW Magnesium; Metal-binding; Multifunctional enzyme; Nucleotide-binding;
KW Transferase.
FT CHAIN 1..740
FT /note="Folic acid synthesis protein fol1"
FT /id="PRO_0000168242"
FT DOMAIN 471..730
FT /note="Pterin-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00334"
FT REGION 39..160
FT /note="DHNA 1"
FT REGION 161..280
FT /note="DHNA 2"
FT REGION 291..449
FT /note="HPPK"
FT REGION 473..740
FT /note="DHPS"
FT BINDING 478
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:P9WND1"
FT BINDING 517
FT /ligand="(7,8-dihydropterin-6-yl)methyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:72950"
FT /evidence="ECO:0000250|UniProtKB:P0AC13"
FT BINDING 552
FT /ligand="(7,8-dihydropterin-6-yl)methyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:72950"
FT /evidence="ECO:0000250|UniProtKB:P0AC13"
FT BINDING 571
FT /ligand="(7,8-dihydropterin-6-yl)methyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:72950"
FT /evidence="ECO:0000250|UniProtKB:P0AC13"
FT BINDING 643
FT /ligand="(7,8-dihydropterin-6-yl)methyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:72950"
FT /evidence="ECO:0000250|UniProtKB:P0AC13"
FT BINDING 683
FT /ligand="(7,8-dihydropterin-6-yl)methyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:72950"
FT /evidence="ECO:0000250|UniProtKB:P0AC13"
FT BINDING 718..720
FT /ligand="(7,8-dihydropterin-6-yl)methyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:72950"
FT /evidence="ECO:0000250|UniProtKB:P0AC13"
FT MUTAGEN 39
FT /note="D->E: Abolishes DHNA activity."
FT /evidence="ECO:0000269|PubMed:9709001"
FT MUTAGEN 53
FT /note="G->A: Reduces DHNA activity 11-fold."
FT /evidence="ECO:0000269|PubMed:9709001"
FT MUTAGEN 63
FT /note="Q->N: Reduces DHNA activity 16-fold."
FT /evidence="ECO:0000269|PubMed:9709001"
FT MUTAGEN 161
FT /note="D->E: No effect."
FT /evidence="ECO:0000269|PubMed:9709001"
FT MUTAGEN 175
FT /note="G->A: Abolishes DHNA activity."
FT /evidence="ECO:0000269|PubMed:9709001"
FT MUTAGEN 185
FT /note="Q->N: Reduces DHNA activity 24-fold."
FT /evidence="ECO:0000269|PubMed:9709001"
SQ SEQUENCE 740 AA; 83962 MW; 328F6EB91B4499EB CRC64;
MIFKSLKIFP FYQIYGFRFL KGMIFKKKIH LSKLNKNHDL IHIHSLTLKS IVGKNSWAQR
LLQPVVLTLS MGINASLSGN MDDLSYSIDY ATVYKEVFKL VENSKFENLL DLSDKISKVV
LGDKCKGNWV KVIAETPKGH LLAETGLQII RRKDGIREID DQFFIKNLSL YTIIGINPEE
RVNKQNIIID LILFKSSINL ECKDDFIINT YNIEKLLKEI VKHVEESTFK TIEALALSIA
RISCISHNIE KIIVKVKKSC ALAFAESAGV EIVRSRSCFS SNNYIKSENS IDNEAVYISL
GSNLGNRIKF ILDAIEKMSI KGIKVLKTSM LYESKPMYFK DQPAFYNAVC KVQTSLHPEQ
LLFELQLIEK ELGRVKVIDK GPRCIDLDIV FYGRKIINSE SLIIPHPRVL ERSFVLKPLL
DISGDLVHPV TGLSIASYFE KIVDHDIKPV LPFLYKNKSI DFSFRSYKAP TYIMAILNLT
PDSFFDGGIH SYDSVLIDVE KFINAGATII DIGGQSTRPG SYIIPLEEEI FRVIPAIKYL
QKTYPDILIS IDTFRSEVAE QAVKAGASLV NDISGGRYDP KMFNTVARLK VPICIMHMRG
NFLNMDNLTD YGTDIIEQIT IELEKLLNSA EKSGIPRWNI ILDPGLGFSK TLHQNIELLR
RFNELKSKNC FNGLPWLLGP SRKRFTGFIT GDNMPKDRIW GTVAAVVASI SGGCDIIRVH
DVYEMYKISK MSDAIWKEIY
