ATR12_EMENI
ID ATR12_EMENI Reviewed; 1270 AA.
AC A0A1U8QWA2; C8VGV9; Q5B2B2;
DT 23-FEB-2022, integrated into UniProtKB/Swiss-Prot.
DT 10-MAY-2017, sequence version 1.
DT 03-AUG-2022, entry version 24.
DE RecName: Full=Glycine betaine reductase ATRR {ECO:0000303|PubMed:31061132};
DE AltName: Full=Nonribosomal peptide synthetase-like protein ATRR {ECO:0000303|PubMed:31061132};
DE Includes:
DE RecName: Full=Carboxylic acid reductase {ECO:0000303|PubMed:31061132};
DE EC=1.2.1.- {ECO:0000269|PubMed:31061132};
DE Includes:
DE RecName: Full=Aldehyde reductase {ECO:0000303|PubMed:31061132};
DE EC=1.1.1.- {ECO:0000269|PubMed:31061132};
GN Name=ATRR {ECO:0000303|PubMed:31061132}; ORFNames=AN5318, ANIA_05318;
OS Emericella nidulans (strain FGSC A4 / ATCC 38163 / CBS 112.46 / NRRL 194 /
OS M139) (Aspergillus nidulans).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC Aspergillus subgen. Nidulantes.
OX NCBI_TaxID=227321;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=FGSC A4 / ATCC 38163 / CBS 112.46 / NRRL 194 / M139;
RX PubMed=16372000; DOI=10.1038/nature04341;
RA Galagan J.E., Calvo S.E., Cuomo C., Ma L.-J., Wortman J.R., Batzoglou S.,
RA Lee S.-I., Bastuerkmen M., Spevak C.C., Clutterbuck J., Kapitonov V.,
RA Jurka J., Scazzocchio C., Farman M.L., Butler J., Purcell S., Harris S.,
RA Braus G.H., Draht O., Busch S., D'Enfert C., Bouchier C., Goldman G.H.,
RA Bell-Pedersen D., Griffiths-Jones S., Doonan J.H., Yu J., Vienken K.,
RA Pain A., Freitag M., Selker E.U., Archer D.B., Penalva M.A., Oakley B.R.,
RA Momany M., Tanaka T., Kumagai T., Asai K., Machida M., Nierman W.C.,
RA Denning D.W., Caddick M.X., Hynes M., Paoletti M., Fischer R., Miller B.L.,
RA Dyer P.S., Sachs M.S., Osmani S.A., Birren B.W.;
RT "Sequencing of Aspergillus nidulans and comparative analysis with A.
RT fumigatus and A. oryzae.";
RL Nature 438:1105-1115(2005).
RN [2]
RP GENOME REANNOTATION.
RC STRAIN=FGSC A4 / ATCC 38163 / CBS 112.46 / NRRL 194 / M139;
RX PubMed=19146970; DOI=10.1016/j.fgb.2008.12.003;
RA Wortman J.R., Gilsenan J.M., Joardar V., Deegan J., Clutterbuck J.,
RA Andersen M.R., Archer D., Bencina M., Braus G., Coutinho P., von Dohren H.,
RA Doonan J., Driessen A.J., Durek P., Espeso E., Fekete E., Flipphi M.,
RA Estrada C.G., Geysens S., Goldman G., de Groot P.W., Hansen K.,
RA Harris S.D., Heinekamp T., Helmstaedt K., Henrissat B., Hofmann G.,
RA Homan T., Horio T., Horiuchi H., James S., Jones M., Karaffa L.,
RA Karanyi Z., Kato M., Keller N., Kelly D.E., Kiel J.A., Kim J.M.,
RA van der Klei I.J., Klis F.M., Kovalchuk A., Krasevec N., Kubicek C.P.,
RA Liu B., Maccabe A., Meyer V., Mirabito P., Miskei M., Mos M., Mullins J.,
RA Nelson D.R., Nielsen J., Oakley B.R., Osmani S.A., Pakula T., Paszewski A.,
RA Paulsen I., Pilsyk S., Pocsi I., Punt P.J., Ram A.F., Ren Q., Robellet X.,
RA Robson G., Seiboth B., van Solingen P., Specht T., Sun J.,
RA Taheri-Talesh N., Takeshita N., Ussery D., vanKuyk P.A., Visser H.,
RA van de Vondervoort P.J., de Vries R.P., Walton J., Xiang X., Xiong Y.,
RA Zeng A.P., Brandt B.W., Cornell M.J., van den Hondel C.A., Visser J.,
RA Oliver S.G., Turner G.;
RT "The 2008 update of the Aspergillus nidulans genome annotation: a community
RT effort.";
RL Fungal Genet. Biol. 46:S2-13(2009).
RN [3]
RP FUNCTION, DISRUPTION PHENOTYPE, DOMAIN, CATALYTIC ACTIVITY, SUBSTRATE
RP SPECIFICITY, BIOPHYSICOCHEMICAL PROPERTIES, MUTAGENESIS OF TYR-812;
RP GLY-1036 AND TYR-1178, AND ACTIVITY REGULATION.
RX PubMed=31061132; DOI=10.1073/pnas.1903282116;
RA Hai Y., Huang A.M., Tang Y.;
RT "Structure-guided function discovery of an NRPS-like glycine betaine
RT reductase for choline biosynthesis in fungi.";
RL Proc. Natl. Acad. Sci. U.S.A. 116:10348-10353(2019).
CC -!- FUNCTION: NRPS-like enzyme with an unusual domain architecture that
CC converts back glycine betaine to choline via a 2-step reduction
CC mechanism, and thereby can be an alternative source of choline
CC (PubMed:31061132). Permits direct reutilization of endogenously stored
CC glycine betaine for on-demand biosynthesis of choline and choline
CC derivatives, including phospholipid phosphatidylcholine (PC) which has
CC an essential role in maintaining membrane integrity and functionality,
CC or choline-O-sulfate, a mean for intracellular sulfate storage
CC (PubMed:31061132). Glycine betaine is activated by the adenylation (A)
CC domain, and transferred to the thiolation (T) domain (PubMed:31061132).
CC Movement of the phosphopantetheine arm to the thioester reductase
CC domain R1 then allows thioester reduction by NADPH of glycine betainoyl
CC thioester to glycine betaine aldehyde, which is in turn reduced to
CC choline by the aldehyde reductase domain R2 (PubMed:31061132).
CC {ECO:0000269|PubMed:31061132}.
CC -!- ACTIVITY REGULATION: The tetramethylammonium ion, which mimics the head
CC group of glycine betaine, acts as a competitive inhibitor of ATRR A
CC domain, whereas the potency decreased by three orders of magnitude with
CC dimethylammonium (PubMed:31061132). Choline is a mixed inhibitor for
CC both glycine betaine reductase and aldehyde reductase activity but more
CC potent in competition against glycine betaine in the first reduction
CC step (PubMed:31061132). Therefore, choline could act as a feedback
CC inhibitor to regulate ATRR enzymatic activity (PubMed:31061132). The
CC lowered binding affinity of choline to R2 favors the release of choline
CC after glycine betaine aldehyde reduction to avoid direct product
CC inhibition (PubMed:31061132). {ECO:0000269|PubMed:31061132}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=2.1 mM for glycine betaine {ECO:0000269|PubMed:31061132};
CC KM=0.24 mM for glycine betaine aldehyde
CC {ECO:0000269|PubMed:31061132};
CC KM=5.8 mM for N,N-dimethylglycine {ECO:0000269|PubMed:31061132};
CC KM=90 mM for 3,3,-dimethylbutyraldehyde (for the aldehyde reductase
CC R2 domain alone) {ECO:0000269|PubMed:31061132};
CC -!- DOMAIN: The NRPS-like protein ATRR has an unusual domain arcitecture
CC (A-T-R1-R2), with the adenylation domain A activating and
CC thioesterifying glycine betaine which is then channeled through the
CC phosphopantetheine arm of the T domain, the thioester reductase domain
CC R1 reducing glycine betainoyl thioester to glycine betaine aldehyde,
CC and the aldehyde reductase domain R2 converting glycine betaine
CC aldehyde into choline. {ECO:0000269|PubMed:31061132}.
CC -!- DISRUPTION PHENOTYPE: Severely impairs the hyphae growth and
CC conidiation at high level glycine betaine (PubMed:31061132). Exhibits a
CC choline-auxotroph character, when the phosphatidylethanolamine N-
CC methyltransferase choA is also deleted (PubMed:31061132).
CC {ECO:0000269|PubMed:31061132}.
CC -!- SIMILARITY: Belongs to the NRP synthetase family. {ECO:0000305}.
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DR EMBL; AACD01000093; EAA62478.1; -; Genomic_DNA.
DR EMBL; BN001305; CBF82109.1; -; Genomic_DNA.
DR RefSeq; XP_662922.1; XM_657830.1.
DR SMR; A0A1U8QWA2; -.
DR STRING; 162425.CADANIAP00003778; -.
DR EnsemblFungi; CBF82109; CBF82109; ANIA_05318.
DR EnsemblFungi; EAA62478; EAA62478; AN5318.2.
DR GeneID; 2871610; -.
DR KEGG; ani:AN5318.2; -.
DR VEuPathDB; FungiDB:AN5318; -.
DR eggNOG; KOG1178; Eukaryota.
DR eggNOG; KOG1205; Eukaryota.
DR HOGENOM; CLU_000022_2_17_1; -.
DR OMA; WRDSIME; -.
DR OrthoDB; 87239at2759; -.
DR Proteomes; UP000000560; Chromosome V.
DR Proteomes; UP000005890; Unassembled WGS sequence.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0009058; P:biosynthetic process; IEA:UniProt.
DR CDD; cd05235; SDR_e1; 1.
DR Gene3D; 1.10.1200.10; -; 1.
DR Gene3D; 3.30.300.30; -; 1.
DR Gene3D; 3.40.50.12780; -; 1.
DR InterPro; IPR036736; ACP-like_sf.
DR InterPro; IPR045851; AMP-bd_C_sf.
DR InterPro; IPR020845; AMP-binding_CS.
DR InterPro; IPR000873; AMP-dep_Synth/Lig.
DR InterPro; IPR042099; ANL_N_sf.
DR InterPro; IPR013120; Far_NAD-bd.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR020806; PKS_PP-bd.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR006162; Ppantetheine_attach_site.
DR InterPro; IPR002347; SDR_fam.
DR InterPro; IPR010080; Thioester_reductase-like_dom.
DR Pfam; PF00106; adh_short; 1.
DR Pfam; PF00501; AMP-binding; 1.
DR Pfam; PF07993; NAD_binding_4; 1.
DR Pfam; PF00550; PP-binding; 1.
DR PRINTS; PR00081; GDHRDH.
DR SMART; SM00823; PKS_PP; 1.
DR SUPFAM; SSF47336; SSF47336; 1.
DR SUPFAM; SSF51735; SSF51735; 2.
DR TIGRFAMs; TIGR01746; Thioester-redct; 1.
DR PROSITE; PS00455; AMP_BINDING; 1.
DR PROSITE; PS50075; CARRIER; 1.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 1: Evidence at protein level;
KW Multifunctional enzyme; Oxidoreductase; Phosphopantetheine; Phosphoprotein;
KW Reference proteome; Repeat.
FT CHAIN 1..1270
FT /note="Glycine betaine reductase ATRR"
FT /id="PRO_0000454493"
FT DOMAIN 528..605
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 14..418
FT /note="Adenylation (A) domain"
FT /evidence="ECO:0000269|PubMed:31061132"
FT REGION 643..937
FT /note="Carboxylic acid reductase domain R1"
FT /evidence="ECO:0000269|PubMed:31061132"
FT REGION 1026..1256
FT /note="Aldehyde reductase domain R2"
FT /evidence="ECO:0000269|PubMed:31061132"
FT MOD_RES 565
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MUTAGEN 812
FT /note="Y->F: Abolishes overall carboxylic acid reductase
FT activity but does nor affect aldehyde reductase activity."
FT /evidence="ECO:0000269|PubMed:31061132"
FT MUTAGEN 1036
FT /note="G->A: Compromises binding of the cosubstrate NADPH
FT to aldehyde reductase domain R2. Decreases the aldehyde
FT reductase activity by 4,000-fold; when associated with F-
FT 1178."
FT /evidence="ECO:0000269|PubMed:31061132"
FT MUTAGEN 1178
FT /note="Y->F: Does not substantially affect carboxylic acid
FT reductase activity but results to a 150-fold loss of
FT aldehyde reductase activity and the accumulation of glycine
FT betaine aldehyde intermediate. Further decreases the
FT aldehyde reductase activity by 4,000-fold; when associated
FT with F-1178."
FT /evidence="ECO:0000269|PubMed:31061132"
SQ SEQUENCE 1270 AA; 137536 MW; 94B5A835044F589B CRC64;
MAIIDTTKDL SALFTQQVRA SPNALALEDD KTSYTYAELD KEVEELSRRL RSYGVSRDSL
VGVLLPRSAH FVIACLAALR AGGAFLVLEL AYPPDLLADV LEDATPAVVV THRSETGKIK
GSVPVISLDE PPVDANGHTV EPGPLPVDDD LDRLAFVSYS SGTTGKPKGI ANPHRAPVLS
YNLRFGVQDL QPGDRVACNV FFIWEILRPL IRGATVVAVP DDHSYDPAAL VDLLASRHIT
ETLMTPTLLA TILSRHSDIG ARLPELRTLW LNGEVVTTDL ARRAIRALPN TRLLNCYSAC
ETHEIACGDI KEIVSDESQY CPVGPLLDPK HAYIVNEQGE KVEEGVSGEL CVGGPMLARG
YINRPETTAK AFIPDPFSNS PGAVMYRTGD RARMLPSGLL EITGRVGAMI KLRGYSVVPG
KVENDIVKHL AVRQCAVVAH GEGLERQLVA YIVADQEHSE ERPTVEINSS GHSPGARRAL
TKFLAHYMIP ALWVQVDELP THEVSGKIDL KRLPPPPTEV LANGNGKKED PIGIEDIAAI
WAVALKVPKA TLKPEDNFFD LGGHSLSIAD LSSRLSRKFG FRIPIVRLAE NSTLSGHLDT
VRAIRDGHTA AVQADLPAVL RTDATLDEEI RSDAKICSLT DAKTVLLTGV TGFLGAFLLK
DLVDSTSAHI ICLVRFNEPE DDDQPGGVAR IRRNLLDLGL WNDSIMERVE ILPGNLSRSR
FGLTPDAFQE LAQRVDVIVH AAASVNLVYP YAALRAANVG GTREILRLAS QGGATVQYVS
TNGVLPPSGE KGWPEDTMLD MKDVPTKLLD GYGQTKWVAE QLVLEAGRRG LPVRVHRIGT
VSGHSQSGAA NAWDLLTALI VESIKLGKYP DVEGWRAEMT PVDFVSKAII HLANQTAVEQ
TVFHIGDPDP VNTRSVFEDL KTLGYPTEPL SWDDWVALWT SQRGHVKGGD GGFTVDILRS
GMPSIEFLRG IVVLDNSATR PIRREVERPK VDRFLLETYT RHWFARGWLK RPPIRQRQLS
PIPKGPLSGK VAVVTGASSG IGAAVATALA REGAHVALGA RRLDALESLK EKLSASGVKV
VTCKTDVTDR KQVEGLVKAA TEELGPVDIL VACAGVMYFT MMANTQMDEW ERTVDVNCKG
ILNSLASTVP GMLARGKGHV VAISSDAGRK VFPGLGVYSA SKFFVEATLQ ALRLETAGQG
LRVTAVQPGN TATDLLGMST DAEAIKKYGE PSGAQILDPE DVANSIIYAL RQPEHVAMNE
ILIEPRDEPI
