ID   AK2H_ECOLI              Reviewed;         810 AA.
AC   P00562; P77856; Q2M8N6;
DT   21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT   23-JAN-2007, sequence version 3.
DT   04-NOV-2026, entry version 203.
DE   RecName: Full=Bifunctional aspartokinase/homoserine dehydrogenase 2;
DE   AltName: Full=Aspartokinase II/homoserine dehydrogenase II;
DE            Short=AKII-HDII;
DE   Includes:
DE     RecName: Full=Aspartokinase;
DE              EC=2.7.2.4;
DE   Includes:
DE     RecName: Full=Homoserine dehydrogenase;
DE              EC=1.1.1.3;
GN   Name=metL; Synonyms=metM; OrderedLocusNames=b3940, JW3911;
OS   Escherichia coli (strain K12).
OC   Bacteria; Pseudomonadati; Pseudomonadota; Gammaproteobacteria;
OC   Enterobacterales; Enterobacteriaceae; Escherichia.
OX   NCBI_TaxID=83333;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND PROTEIN SEQUENCE OF 2-10.
RX   PubMed=6298218; DOI=10.1016/s0021-9258(18)32824-2;
RA   Zakin M.M., Duchange N., Ferrara P., Cohen G.N.;
RT   "Nucleotide sequence of the metL gene of Escherichia coli. Its product, the
RT   bifunctional aspartokinase II-homoserine dehydrogenase II, and the
RT   bifunctional product of the thrA gene, aspartokinase I-homoserine
RT   dehydrogenase I, derive from a common ancestor.";
RL   J. Biol. Chem. 258:3028-3031(1983).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=K12 / MG1655 / ATCC 47076;
RX   PubMed=8346018; DOI=10.1093/nar/21.15.3391;
RA   Plunkett G. III, Burland V., Daniels D.L., Blattner F.R.;
RT   "Analysis of the Escherichia coli genome. III. DNA sequence of the region
RT   from 87.2 to 89.2 minutes.";
RL   Nucleic Acids Res. 21:3391-3398(1993).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=K12 / MG1655 / ATCC 47076;
RX   PubMed=9278503; DOI=10.1126/science.277.5331.1453;
RA   Blattner F.R., Plunkett G. III, Bloch C.A., Perna N.T., Burland V.,
RA   Riley M., Collado-Vides J., Glasner J.D., Rode C.K., Mayhew G.F.,
RA   Gregor J., Davis N.W., Kirkpatrick H.A., Goeden M.A., Rose D.J., Mau B.,
RA   Shao Y.;
RT   "The complete genome sequence of Escherichia coli K-12.";
RL   Science 277:1453-1462(1997).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=K12 / W3110 / ATCC 27325 / DSM 5911;
RX   PubMed=16738553; DOI=10.1038/msb4100049;
RA   Hayashi K., Morooka N., Yamamoto Y., Fujita K., Isono K., Choi S.,
RA   Ohtsubo E., Baba T., Wanner B.L., Mori H., Horiuchi T.;
RT   "Highly accurate genome sequences of Escherichia coli K-12 strains MG1655
RT   and W3110.";
RL   Mol. Syst. Biol. 2:E1-E5(2006).
CC   -!- FUNCTION: Bifunctional aspartate kinase and homoserine dehydrogenase
CC       that catalyzes the first and the third steps toward the synthesis of
CC       lysine, methionine and threonine from aspartate.
CC       {ECO:0000250|UniProtKB:Q9SA18}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-homoserine + NADP(+) = L-aspartate 4-semialdehyde + NADPH +
CC         H(+); Xref=Rhea:RHEA:15761, ChEBI:CHEBI:15378, ChEBI:CHEBI:57476,
CC         ChEBI:CHEBI:57783, ChEBI:CHEBI:58349, ChEBI:CHEBI:537519; EC=1.1.1.3;
CC         Evidence={ECO:0000250|UniProtKB:Q9SA18};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:15763;
CC         Evidence={ECO:0000250|UniProtKB:Q9SA18};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-homoserine + NAD(+) = L-aspartate 4-semialdehyde + NADH +
CC         H(+); Xref=Rhea:RHEA:15757, ChEBI:CHEBI:15378, ChEBI:CHEBI:57476,
CC         ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:537519; EC=1.1.1.3;
CC         Evidence={ECO:0000250|UniProtKB:Q9SA18};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:15759;
CC         Evidence={ECO:0000250|UniProtKB:Q9SA18};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=L-aspartate + ATP = 4-phospho-L-aspartate + ADP;
CC         Xref=Rhea:RHEA:23776, ChEBI:CHEBI:29991, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:57535, ChEBI:CHEBI:456216; EC=2.7.2.4;
CC         Evidence={ECO:0000250|UniProtKB:Q9SA18};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:23777;
CC         Evidence={ECO:0000250|UniProtKB:Q9SA18};
CC   -!- COFACTOR:
CC       Name=a metal cation; Xref=ChEBI:CHEBI:25213;
CC         Evidence={ECO:0000250|UniProtKB:P31116};
CC       Note=A sodium ion is seen in the structure; a metal ion may subtly
CC       affect the relative position of the nucleotide-binding region to
CC       influence enzyme activity, and could increase the stability of the
CC       enzyme. {ECO:0000250|UniProtKB:P31116};
CC   -!- PATHWAY: Amino-acid biosynthesis; L-lysine biosynthesis via DAP
CC       pathway; (S)-tetrahydrodipicolinate from L-aspartate: step 1/4.
CC       {ECO:0000250|UniProtKB:Q9SA18}.
CC   -!- PATHWAY: Amino-acid biosynthesis; L-methionine biosynthesis via de novo
CC       pathway; L-homoserine from L-aspartate: step 1/3.
CC       {ECO:0000250|UniProtKB:Q9SA18}.
CC   -!- PATHWAY: Amino-acid biosynthesis; L-methionine biosynthesis via de novo
CC       pathway; L-homoserine from L-aspartate: step 3/3.
CC       {ECO:0000250|UniProtKB:Q9SA18}.
CC   -!- PATHWAY: Amino-acid biosynthesis; L-threonine biosynthesis; L-threonine
CC       from L-aspartate: step 1/5. {ECO:0000250|UniProtKB:Q9SA18}.
CC   -!- PATHWAY: Amino-acid biosynthesis; L-threonine biosynthesis; L-threonine
CC       from L-aspartate: step 3/5. {ECO:0000250|UniProtKB:Q9SA18}.
CC   -!- SUBUNIT: Homotetramer.
CC   -!- MISCELLANEOUS: Aspartokinase I-homoserine dehydrogenase I and
CC       aspartokinase III also catalyze the same reaction(s).
CC   -!- SIMILARITY: In the N-terminal section; belongs to the aspartokinase
CC       family. {ECO:0000305}.
CC   -!- SIMILARITY: In the C-terminal section; belongs to the homoserine
CC       dehydrogenase family. {ECO:0000305}.
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; V00305; CAA23585.1; -; Genomic_DNA.
DR   EMBL; L19201; AAB03072.1; -; Genomic_DNA.
DR   EMBL; U00096; AAC76922.1; -; Genomic_DNA.
DR   EMBL; AP009048; BAE77370.1; -; Genomic_DNA.
DR   PIR; S40883; DEECK2.
DR   RefSeq; NP_418375.1; NC_000913.3.
DR   RefSeq; WP_000110772.1; NZ_CP009789.1.
DR   AlphaFoldDB; P00562; -.
DR   SMR; P00562; -.
DR   BioGRID; 4261101; 424.
DR   DIP; DIP-10197N; -.
DR   FunCoup; P00562; 496.
DR   IntAct; P00562; 3.
DR   STRING; 511145.b3940; -.
DR   jPOST; P00562; -.
DR   PaxDb; 511145-b3940; -.
DR   EnsemblBacteria; AAC76922; AAC76922; b3940.
DR   GeneID; 75169385; -.
DR   GeneID; 948433; -.
DR   KEGG; ecj:JW3911; -.
DR   KEGG; eco:b3940; -.
DR   KEGG; ecoc:C3026_21290; -.
DR   PATRIC; fig|1411691.4.peg.2765; -.
DR   EchoBASE; EB0585; -.
DR   eggNOG; COG0460; Bacteria.
DR   eggNOG; COG0527; Bacteria.
DR   HOGENOM; CLU_009116_7_2_6; -.
DR   InParanoid; P00562; -.
DR   OMA; AAFHFAH; -.
DR   OrthoDB; 9799110at2; -.
DR   PhylomeDB; P00562; -.
DR   BioCyc; EcoCyc:ASPKINIIHOMOSERDEHYDROGII-MONOMER; -.
DR   BioCyc; MetaCyc:ASPKINIIHOMOSERDEHYDROGII-MONOMER; -.
DR   UniPathway; UPA00034; UER00015.
DR   UniPathway; UPA00050; UER00063.
DR   UniPathway; UPA00050; UER00461.
DR   UniPathway; UPA00051; UER00462.
DR   UniPathway; UPA00051; UER00465.
DR   PRO; PR:P00562; -.
DR   Proteomes; UP000000625; Chromosome.
DR   AbasyAtlas; P00562; -.
DR   GO; GO:0005829; C:cytosol; IDA:EcoCyc.
DR   GO; GO:0004022; F:alcohol dehydrogenase (NAD+) activity; IEA:RHEA.
DR   GO; GO:0004072; F:aspartate kinase activity; IDA:EcoCyc.
DR   GO; GO:0004412; F:homoserine dehydrogenase activity; IDA:EcoCyc.
DR   GO; GO:0070403; F:NAD+ binding; ISS:UniProtKB.
DR   GO; GO:0050661; F:NADP binding; IEA:InterPro.
DR   GO; GO:0009090; P:L-homoserine biosynthetic process; IDA:EcoCyc.
DR   GO; GO:0071265; P:L-methionine biosynthetic process; ISS:UniProtKB.
DR   GO; GO:0009088; P:L-threonine biosynthetic process; ISS:UniProtKB.
DR   CDD; cd04257; AAK_AK-HSDH; 1.
DR   CDD; cd04892; ACT_AK-like_2; 1.
DR   FunFam; 3.40.1160.10:FF:000009; Bifunctional aspartokinase/homoserine dehydrogenase; 1.
DR   FunFam; 3.40.50.720:FF:000124; Bifunctional aspartokinase/homoserine dehydrogenase; 1.
DR   Gene3D; 3.40.1160.10; Acetylglutamate kinase-like; 1.
DR   Gene3D; 1.20.120.1320; Aspartokinase, catalytic domain; 1.
DR   Gene3D; 3.30.360.10; Dihydrodipicolinate Reductase, domain 2; 1.
DR   Gene3D; 3.40.50.720; NAD(P)-binding Rossmann-like Domain; 1.
DR   InterPro; IPR036393; AceGlu_kinase-like_sf.
DR   InterPro; IPR049638; AK-HD.
DR   InterPro; IPR041743; AK-HSDH_N.
DR   InterPro; IPR001048; Asp/Glu/Uridylate_kinase.
DR   InterPro; IPR005106; Asp/hSer_DH_NAD-bd.
DR   InterPro; IPR001341; Asp_kinase.
DR   InterPro; IPR042199; AsparK_Bifunc_asparK/hSer_DH.
DR   InterPro; IPR018042; Aspartate_kinase_CS.
DR   InterPro; IPR011147; Bifunc_Aspkin/hSer_DH.
DR   InterPro; IPR001342; HDH_cat.
DR   InterPro; IPR019811; HDH_CS.
DR   InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR   NCBIfam; TIGR00657; asp_kinases; 1.
DR   NCBIfam; NF007003; metL; 1.
DR   PANTHER; PTHR43070; -; 1.
DR   PANTHER; PTHR43070:SF3; HOMOSERINE DEHYDROGENASE; 1.
DR   Pfam; PF00696; AA_kinase; 1.
DR   Pfam; PF00742; Homoserine_dh; 1.
DR   Pfam; PF03447; NAD_binding_3; 1.
DR   PIRSF; PIRSF000727; ThrA; 1.
DR   SUPFAM; SSF53633; Carbamate kinase-like; 1.
DR   SUPFAM; SSF55347; Glyceraldehyde-3-phosphate dehydrogenase-like, C-terminal domain; 1.
DR   SUPFAM; SSF51735; NAD(P)-binding Rossmann-fold domains; 1.
DR   PROSITE; PS00324; ASPARTOKINASE; 1.
DR   PROSITE; PS01042; HOMOSER_DHGENASE; 1.
PE   1: Evidence at protein level;
KW   Amino-acid biosynthesis; ATP-binding; Direct protein sequencing; Kinase;
KW   Lysine biosynthesis; Metal-binding; Methionine biosynthesis;
KW   Multifunctional enzyme; NAD; NADP; Nucleotide-binding; Oxidoreductase;
KW   Reference proteome; Sodium; Threonine biosynthesis; Transferase.
FT   INIT_MET        1
FT                   /note="Removed"
FT                   /evidence="ECO:0000269|PubMed:6298218"
FT   CHAIN           2..810
FT                   /note="Bifunctional aspartokinase/homoserine dehydrogenase
FT                   2"
FT                   /id="PRO_0000066683"
FT   REGION          2..252
FT                   /note="Aspartokinase"
FT   REGION          253..463
FT                   /note="Interface"
FT   REGION          464..810
FT                   /note="Homoserine dehydrogenase"
FT   ACT_SITE        676
FT                   /note="Proton donor"
FT                   /evidence="ECO:0000255"
FT   BINDING         468
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250|UniProtKB:F9VNG5"
FT   BINDING         469
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000250|UniProtKB:P31116"
FT   BINDING         469
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250|UniProtKB:F9VNG5"
FT   BINDING         469
FT                   /ligand="NADPH"
FT                   /ligand_id="ChEBI:CHEBI:57783"
FT                   /evidence="ECO:0000250|UniProtKB:O58802"
FT   BINDING         498
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000250|UniProtKB:P31116"
FT   BINDING         501
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250|UniProtKB:F9VNG5"
FT   BINDING         549
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000250|UniProtKB:P31116"
FT   BINDING         549
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250|UniProtKB:F9VNG5"
FT   BINDING         549
FT                   /ligand="NADPH"
FT                   /ligand_id="ChEBI:CHEBI:57783"
FT                   /evidence="ECO:0000250|UniProtKB:O58802"
FT   BINDING         573
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250|UniProtKB:F9VNG5"
FT   BINDING         573
FT                   /ligand="NADPH"
FT                   /ligand_id="ChEBI:CHEBI:57783"
FT                   /evidence="ECO:0000250|UniProtKB:O58802"
FT   BINDING         603
FT                   /ligand="Na(+)"
FT                   /ligand_id="ChEBI:CHEBI:29101"
FT                   /evidence="ECO:0000250|UniProtKB:P31116"
FT   BINDING         605
FT                   /ligand="Na(+)"
FT                   /ligand_id="ChEBI:CHEBI:29101"
FT                   /evidence="ECO:0000250|UniProtKB:P31116"
FT   BINDING         607
FT                   /ligand="Na(+)"
FT                   /ligand_id="ChEBI:CHEBI:29101"
FT                   /evidence="ECO:0000250|UniProtKB:P31116"
FT   BINDING         658
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250|UniProtKB:F9VNG5"
FT   BINDING         661
FT                   /ligand="L-homoserine"
FT                   /ligand_id="ChEBI:CHEBI:57476"
FT                   /evidence="ECO:0000250|UniProtKB:P31116"
FT   BINDING         661
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250|UniProtKB:F9VNG5"
FT   BINDING         672
FT                   /ligand="L-homoserine"
FT                   /ligand_id="ChEBI:CHEBI:57476"
FT                   /evidence="ECO:0000250|UniProtKB:P31116"
FT   BINDING         791
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000250|UniProtKB:P31116"
FT   BINDING         791
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250|UniProtKB:F9VNG5"
FT   BINDING         791
FT                   /ligand="NADPH"
FT                   /ligand_id="ChEBI:CHEBI:57783"
FT                   /evidence="ECO:0000250|UniProtKB:O58802"
FT   CONFLICT        56
FT                   /note="Q -> R (in Ref. 1; CAA23585)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        59
FT                   /note="N -> S (in Ref. 1; CAA23585)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        333
FT                   /note="A -> G (in Ref. 1; CAA23585)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        674
FT                   /note="M -> S (in Ref. 1; CAA23585)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        762
FT                   /note="A -> R (in Ref. 1; CAA23585)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   810 AA;  88888 MW;  BD2515E3554F9B44 CRC64;
     MSVIAQAGAK GRQLHKFGGS SLADVKCYLR VAGIMAEYSQ PDDMMVVSAA GSTTNQLINW
     LKLSQTDRLS AHQVQQTLRR YQCDLISGLL PAEEADSLIS AFVSDLERLA ALLDSGINDA
     VYAEVVGHGE VWSARLMSAV LNQQGLPAAW LDAREFLRAE RAAQPQVDEG LSYPLLQQLL
     VQHPGKRLVV TGFISRNNAG ETVLLGRNGS DYSATQIGAL AGVSRVTIWS DVAGVYSADP
     RKVKDACLLP LLRLDEASEL ARLAAPVLHA RTLQPVSGSE IDLQLRCSYT PDQGSTRIER
     VLASGTGARI VTSHDDVCLI EFQVPASQDF KLAHKEIDQI LKRAQVRPLA VGVHNDRQLL
     QFCYTSEVAD SALKILDEAG LPGELRLRQG LALVAMVGAG VTRNPLHCHR FWQQLKGQPV
     EFTWQSDDGI SLVAVLRTGP TESLIQGLHQ SVFRAEKRIG LVLFGKGNIG SRWLELFARE
     QSTLSARTGF EFVLAGVVDS RRSLLSYDGL DASRALAFFN DEAVEQDEES LFLWMRAHPY
     DDLVVLDVTA SQQLADQYLD FASHGFHVIS ANKLAGASDS NKYRQIHDAF EKTGRHWLYN
     ATVGAGLPIN HTVRDLIDSG DTILSISGIF SGTLSWLFLQ FDGSVPFTEL VDQAWQQGLT
     EPDPRDDLSG KDVMRKLVIL AREAGYNIEP DQVRVESLVP AHCEGGSIDH FFENGDELNE
     QMVQRLEAAR EMGLVLRYVA RFDANGKARV GVEAVREDHP LASLLPCDNV FAIESRWYRD
     NPLVIRGPGA GRDVTAGAIQ SDINRLAQLL
//