DHAS_MYCTU
ID DHAS_MYCTU Reviewed; 345 AA.
AC P9WNX5; L0TDK5; P0A542; P47730; P97049; Q597F4;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 45.
DE RecName: Full=Aspartate-semialdehyde dehydrogenase {ECO:0000303|PubMed:18323599};
DE Short=ASA dehydrogenase;
DE Short=ASADH {ECO:0000303|PubMed:18323599};
DE EC=1.2.1.11 {ECO:0000269|PubMed:15752328, ECO:0000269|PubMed:18323599};
DE AltName: Full=Aspartate-beta-semialdehyde dehydrogenase {ECO:0000303|PubMed:15752328};
GN Name=asd {ECO:0000303|PubMed:18323599}; OrderedLocusNames=Rv3708c;
GN ORFNames=MTV025.056c;
OS Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv).
OC Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae;
OC Mycobacterium; Mycobacterium tuberculosis complex.
OX NCBI_TaxID=83332;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Gilker J.M., Jucker M.T.;
RT "Mycobacterium tuberculosis ask-alpha, ask-beta and asd genes.";
RL Submitted (FEB-1997) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, CATALYTIC ACTIVITY, AND
RP KINETIC PARAMETERS.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=15752328; DOI=10.1111/j.1365-2672.2004.02505.x;
RA Shafiani S., Sharma P., Vohra R.M., Tewari R.;
RT "Cloning and characterization of aspartate-beta-semialdehyde dehydrogenase
RT from Mycobacterium tuberculosis H37 Rv.";
RL J. Appl. Microbiol. 98:832-838(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=9634230; DOI=10.1038/31159;
RA Cole S.T., Brosch R., Parkhill J., Garnier T., Churcher C.M., Harris D.E.,
RA Gordon S.V., Eiglmeier K., Gas S., Barry C.E. III, Tekaia F., Badcock K.,
RA Basham D., Brown D., Chillingworth T., Connor R., Davies R.M., Devlin K.,
RA Feltwell T., Gentles S., Hamlin N., Holroyd S., Hornsby T., Jagels K.,
RA Krogh A., McLean J., Moule S., Murphy L.D., Oliver S., Osborne J.,
RA Quail M.A., Rajandream M.A., Rogers J., Rutter S., Seeger K., Skelton S.,
RA Squares S., Squares R., Sulston J.E., Taylor K., Whitehead S.,
RA Barrell B.G.;
RT "Deciphering the biology of Mycobacterium tuberculosis from the complete
RT genome sequence.";
RL Nature 393:537-544(1998).
RN [4]
RP CRYSTALLIZATION, CATALYTIC ACTIVITY, AND SUBUNIT.
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=18323599; DOI=10.1107/s1744309108002753;
RA Vyas R., Kumar V., Panjikar S., Karthikeyan S., Kishan K.V., Tewari R.,
RA Weiss M.S.;
RT "Purification, crystallization and preliminary X-ray diffraction analysis
RT of aspartate semialdehyde dehydrogenase (Rv3708c) from Mycobacterium
RT tuberculosis.";
RL Acta Crystallogr. F 64:167-170(2008).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=21969609; DOI=10.1074/mcp.m111.011627;
RA Kelkar D.S., Kumar D., Kumar P., Balakrishnan L., Muthusamy B., Yadav A.K.,
RA Shrivastava P., Marimuthu A., Anand S., Sundaram H., Kingsbury R.,
RA Harsha H.C., Nair B., Prasad T.S., Chauhan D.S., Katoch K., Katoch V.M.,
RA Kumar P., Chaerkady R., Ramachandran S., Dash D., Pandey A.;
RT "Proteogenomic analysis of Mycobacterium tuberculosis by high resolution
RT mass spectrometry.";
RL Mol. Cell. Proteomics 10:M111.011627-M111.011627(2011).
RN [6]
RP 3D-STRUCTURE MODELING.
RC STRAIN=H37Rv;
RX PubMed=18236087; DOI=10.1007/s00894-008-0267-2;
RA Singh A., Kushwaha H.R., Sharma P.;
RT "Molecular modelling and comparative structural account of aspartyl beta-
RT semialdehyde dehydrogenase of Mycobacterium tuberculosis (H37Rv).";
RL J. Mol. Model. 14:249-263(2008).
RN [7]
RP DISRUPTION PHENOTYPE, AND IDENTIFICATION AS A DRUG TARGET.
RC STRAIN=H37Rv;
RX PubMed=26437401; DOI=10.3390/ijms161023572;
RA Meng J., Yang Y., Xiao C., Guan Y., Hao X., Deng Q., Lu Z.;
RT "Identification and validation of aspartic acid semialdehyde dehydrogenase
RT as a new anti-Mycobacterium tuberculosis target.";
RL Int. J. Mol. Sci. 16:23572-23586(2015).
RN [8]
RP IN SILICO IDENTIFICATION OF INHIBITORS.
RX PubMed=25565373; DOI=10.1080/07391102.2015.1005137;
RA Kumar R., Garg P., Bharatam P.V.;
RT "Pharmacoinformatics analysis to identify inhibitors of Mtb-ASADH.";
RL J. Biomol. Struct. Dyn. 11:1-14(2015).
RN [9]
RP IN SILICO IDENTIFICATION OF INHIBITORS.
RX PubMed=24875451; DOI=10.1080/07391102.2014.929535;
RA Kumar R., Garg P., Bharatam P.V.;
RT "Shape-based virtual screening, docking, and molecular dynamics simulations
RT to identify Mtb-ASADH inhibitors.";
RL J. Biomol. Struct. Dyn. 33:1082-1093(2015).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 2-345, ACTIVE SITE, AND SUBUNIT.
RC STRAIN=H37Rv;
RX PubMed=22683789; DOI=10.1107/s0907444912007330;
RA Vyas R., Tewari R., Weiss M.S., Karthikeyan S.;
RT "Structures of ternary complexes of aspartate-semialdehyde dehydrogenase
RT (Rv3708c) from Mycobacterium tuberculosis H37Rv.";
RL Acta Crystallogr. D 68:671-679(2012).
CC -!- FUNCTION: Catalyzes the NADPH-dependent formation of L-aspartate-
CC semialdehyde (L-ASA) by the reductive dephosphorylation of L-aspartyl-
CC 4-phosphate (PubMed:15752328). Is essential for the growth and
CC pathogenicity of M.tuberculosis, and for the generation of the
CC bacterial cell wall (PubMed:26437401). {ECO:0000269|PubMed:15752328,
CC ECO:0000269|PubMed:26437401}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-aspartate 4-semialdehyde + NADP(+) + phosphate = 4-phospho-
CC L-aspartate + H(+) + NADPH; Xref=Rhea:RHEA:24284, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:57535, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349, ChEBI:CHEBI:537519; EC=1.2.1.11;
CC Evidence={ECO:0000269|PubMed:15752328, ECO:0000269|PubMed:18323599};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=955 uM for L-aspartate 4-semialdehyde
CC {ECO:0000269|PubMed:15752328};
CC KM=65 uM for NADP(+) {ECO:0000269|PubMed:15752328};
CC KM=11.4 mM for phosphate {ECO:0000269|PubMed:15752328};
CC Vmax=51.84 umol/min/mg enzyme towards L-aspartate 4-semialdehyde
CC {ECO:0000269|PubMed:15752328};
CC Vmax=43.74 umol/min/mg enzyme towards NADP(+)
CC {ECO:0000269|PubMed:15752328};
CC Vmax=44.04 umol/min/mg enzyme towards phosphate
CC {ECO:0000269|PubMed:15752328};
CC -!- PATHWAY: Amino-acid biosynthesis; L-lysine biosynthesis via DAP
CC pathway; (S)-tetrahydrodipicolinate from L-aspartate: step 2/4.
CC -!- PATHWAY: Amino-acid biosynthesis; L-methionine biosynthesis via de novo
CC pathway; L-homoserine from L-aspartate: step 2/3.
CC -!- PATHWAY: Amino-acid biosynthesis; L-threonine biosynthesis; L-threonine
CC from L-aspartate: step 2/5.
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:18323599,
CC ECO:0000269|PubMed:22683789}.
CC -!- DISRUPTION PHENOTYPE: Deletion of this gene inhibits bacterial growth.
CC The mutant cells lose an average of 77.8% of their cell wall materials,
CC exhibit altered morphology, and have a reduced capacity to infect
CC macrophages. {ECO:0000269|PubMed:26437401}.
CC -!- SIMILARITY: Belongs to the aspartate-semialdehyde dehydrogenase family.
CC {ECO:0000305}.
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DR EMBL; U90239; AAB49996.1; -; Genomic_DNA.
DR EMBL; AY372113; AAQ75346.1; -; Genomic_DNA.
DR EMBL; AL123456; CCP46534.1; -; Genomic_DNA.
DR PIR; E70794; E70794.
DR RefSeq; NP_218225.1; NC_000962.3.
DR RefSeq; WP_003419825.1; NZ_NVQJ01000009.1.
DR PDB; 3TZ6; X-ray; 1.95 A; A=2-345.
DR PDB; 3VOS; X-ray; 2.18 A; A=2-345.
DR PDBsum; 3TZ6; -.
DR PDBsum; 3VOS; -.
DR AlphaFoldDB; P9WNX5; -.
DR SMR; P9WNX5; -.
DR STRING; 83332.Rv3708c; -.
DR PaxDb; P9WNX5; -.
DR GeneID; 885118; -.
DR KEGG; mtu:Rv3708c; -.
DR TubercuList; Rv3708c; -.
DR eggNOG; COG0136; Bacteria.
DR OMA; CEEEMKM; -.
DR PhylomeDB; P9WNX5; -.
DR BRENDA; 1.2.1.11; 3445.
DR SABIO-RK; P9WNX5; -.
DR UniPathway; UPA00034; UER00016.
DR UniPathway; UPA00050; UER00463.
DR UniPathway; UPA00051; UER00464.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0009274; C:peptidoglycan-based cell wall; HDA:MTBBASE.
DR GO; GO:0005886; C:plasma membrane; HDA:MTBBASE.
DR GO; GO:0004073; F:aspartate-semialdehyde dehydrogenase activity; IDA:MTBBASE.
DR GO; GO:0051287; F:NAD binding; IEA:InterPro.
DR GO; GO:0050661; F:NADP binding; IEA:UniProtKB-UniRule.
DR GO; GO:0046983; F:protein dimerization activity; IEA:InterPro.
DR GO; GO:0071266; P:'de novo' L-methionine biosynthetic process; IEA:UniProtKB-UniRule.
DR GO; GO:0019877; P:diaminopimelate biosynthetic process; IDA:MTBBASE.
DR GO; GO:0009097; P:isoleucine biosynthetic process; IEA:InterPro.
DR GO; GO:0009089; P:lysine biosynthetic process via diaminopimelate; IDA:MTBBASE.
DR GO; GO:0009088; P:threonine biosynthetic process; IEA:UniProtKB-UniRule.
DR HAMAP; MF_02121; ASADH; 1.
DR InterPro; IPR000319; Asp-semialdehyde_DH_CS.
DR InterPro; IPR012080; Asp_semialdehyde_DH.
DR InterPro; IPR005986; Asp_semialdehyde_DH_beta.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR000534; Semialdehyde_DH_NAD-bd.
DR InterPro; IPR012280; Semialdhyde_DH_dimer_dom.
DR Pfam; PF01118; Semialdhyde_dh; 1.
DR Pfam; PF02774; Semialdhyde_dhC; 1.
DR SMART; SM00859; Semialdhyde_dh; 1.
DR SUPFAM; SSF51735; SSF51735; 1.
DR TIGRFAMs; TIGR01296; asd_B; 1.
DR PROSITE; PS01103; ASD; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Amino-acid biosynthesis; Diaminopimelate biosynthesis;
KW Lysine biosynthesis; Methionine biosynthesis; NADP; Oxidoreductase;
KW Reference proteome; Threonine biosynthesis; Virulence.
FT CHAIN 1..345
FT /note="Aspartate-semialdehyde dehydrogenase"
FT /id="PRO_0000141383"
FT ACT_SITE 130
FT /note="Acyl-thioester intermediate"
FT /evidence="ECO:0000305|PubMed:22683789"
FT ACT_SITE 256
FT /note="Proton acceptor"
FT /evidence="ECO:0000250"
FT BINDING 11..14
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 39..40
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 99
FT /ligand="phosphate"
FT /ligand_id="ChEBI:CHEBI:43474"
FT /evidence="ECO:0000250"
FT BINDING 157
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 160..161
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 227
FT /ligand="phosphate"
FT /ligand_id="ChEBI:CHEBI:43474"
FT /evidence="ECO:0000250"
FT BINDING 249
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 325
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT STRAND 3..9
FT /evidence="ECO:0007829|PDB:3TZ6"
FT HELIX 13..24
FT /evidence="ECO:0007829|PDB:3TZ6"
FT STRAND 29..36
FT /evidence="ECO:0007829|PDB:3TZ6"
FT TURN 38..40
FT /evidence="ECO:0007829|PDB:3TZ6"
FT STRAND 44..47
FT /evidence="ECO:0007829|PDB:3TZ6"
FT STRAND 50..56
FT /evidence="ECO:0007829|PDB:3TZ6"
FT TURN 57..59
FT /evidence="ECO:0007829|PDB:3TZ6"
FT STRAND 66..70
FT /evidence="ECO:0007829|PDB:3TZ6"
FT HELIX 74..86
FT /evidence="ECO:0007829|PDB:3TZ6"
FT STRAND 90..93
FT /evidence="ECO:0007829|PDB:3TZ6"
FT TURN 97..100
FT /evidence="ECO:0007829|PDB:3TZ6"
FT TURN 109..111
FT /evidence="ECO:0007829|PDB:3TZ6"
FT HELIX 113..116
FT /evidence="ECO:0007829|PDB:3TZ6"
FT STRAND 123..126
FT /evidence="ECO:0007829|PDB:3TZ6"
FT HELIX 130..146
FT /evidence="ECO:0007829|PDB:3TZ6"
FT STRAND 148..157
FT /evidence="ECO:0007829|PDB:3TZ6"
FT HELIX 159..162
FT /evidence="ECO:0007829|PDB:3TZ6"
FT HELIX 164..177
FT /evidence="ECO:0007829|PDB:3TZ6"
FT HELIX 178..185
FT /evidence="ECO:0007829|PDB:3TZ6"
FT STRAND 197..201
FT /evidence="ECO:0007829|PDB:3TZ6"
FT STRAND 216..219
FT /evidence="ECO:0007829|PDB:3TZ6"
FT HELIX 223..236
FT /evidence="ECO:0007829|PDB:3TZ6"
FT STRAND 242..246
FT /evidence="ECO:0007829|PDB:3TZ6"
FT STRAND 256..266
FT /evidence="ECO:0007829|PDB:3TZ6"
FT HELIX 270..279
FT /evidence="ECO:0007829|PDB:3TZ6"
FT STRAND 283..285
FT /evidence="ECO:0007829|PDB:3TZ6"
FT HELIX 291..294
FT /evidence="ECO:0007829|PDB:3TZ6"
FT STRAND 298..307
FT /evidence="ECO:0007829|PDB:3TZ6"
FT HELIX 312..314
FT /evidence="ECO:0007829|PDB:3TZ6"
FT STRAND 316..323
FT /evidence="ECO:0007829|PDB:3TZ6"
FT TURN 325..330
FT /evidence="ECO:0007829|PDB:3TZ6"
FT HELIX 331..341
FT /evidence="ECO:0007829|PDB:3TZ6"
SQ SEQUENCE 345 AA; 36230 MW; C886DDB63D03E25D CRC64;
MGLSIGIVGA TGQVGQVMRT LLDERDFPAS AVRFFASARS QGRKLAFRGQ EIEVEDAETA
DPSGLDIALF SAGSAMSKVQ APRFAAAGVT VIDNSSAWRK DPDVPLVVSE VNFERDAHRR
PKGIIANPNC TTMAAMPVLK VLHDEARLVR LVVSSYQAVS GSGLAGVAEL AEQARAVIGG
AEQLVYDGGA LEFPPPNTYV APIAFNVVPL AGSLVDDGSG ETDEDQKLRF ESRKILGIPD
LLVSGTCVRV PVFTGHSLSI NAEFAQPLSP ERARELLDGA TGVQLVDVPT PLAAAGVDES
LVGRIRRDPG VPDGRGLALF VSGDNLRKGA ALNTIQIAEL LTADL
