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Protein

Multifunctional 2-oxoglutarate metabolism enzyme

Gene

kgd

Organism
Mycobacterium smegmatis (strain ATCC 700084 / mc(2)155)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Shows three enzymatic activities that share a first common step, the attack of thiamine-PP on 2-oxoglutarate (alpha-ketoglutarate, KG), leading to the formation of an enamine-thiamine-PP intermediate upon decarboxylation. Thus, displays KGD activity, catalyzing the decarboxylation from five-carbon 2-oxoglutarate to four-carbon succinate semialdehyde (SSA). Also catalyzes C-C bond formation between the activated aldehyde formed after decarboxylation of alpha-ketoglutarate and the carbonyl of glyoxylate (GLX), to yield 2-hydroxy-3-oxoadipate (HOA), which spontaneously decarboxylates to form 5-hydroxylevulinate (HLA). And is also a component of the 2-oxoglutarate dehydrogenase (ODH) complex, that catalyzes the overall conversion of 2-oxoglutarate to succinyl-CoA and CO2. The KG decarboxylase and KG dehydrogenase reactions provide two alternative, tightly regulated, pathways connecting the oxidative and reductive branches of the TCA cycle.2 Publications

Catalytic activityi

2-oxoglutarate + glyoxylate = 2-hydroxy-3-oxoadipate + CO2.1 Publication
2-oxoglutarate = succinate semialdehyde + CO2.1 Publication
2-oxoglutarate + [dihydrolipoyllysine-residue succinyltransferase] lipoyllysine = [dihydrolipoyllysine-residue succinyltransferase] S-succinyldihydrolipoyllysine + CO2.1 Publication
Succinyl-CoA + enzyme N6-(dihydrolipoyl)lysine = CoA + enzyme N6-(S-succinyldihydrolipoyl)lysine.1 Publication

Cofactori

Protein has several cofactor binding sites:
  • Mg2+1 Publication
  • thiamine diphosphate1 Publication

Enzyme regulationi

Alpha-ketoglutarate dehydrogenase and decarboxylase activities are inhibited by unphosphorylated GarA, and allosterically activated by acetyl-CoA, the main substrate of the TCA cycle. Both the phosphoadenosine and acetyl moieties of acetyl-CoA are important for activation because neither CoA nor the synthetic compound S-(2-acetamidoethyl)-ethanethioate (which mimics the terminal acetyl-phosphopantetheine group of acetyl-CoA) has an activation effect.2 Publications

Kineticsi

  1. KM=0.54 mM for alpha-ketoglutarate1 Publication

    Pathwayi: tricarboxylic acid cycle

    This protein is involved in step 1 of the subpathway that synthesizes succinate from 2-oxoglutarate (transferase route).1 Publication
    Proteins known to be involved in the 2 steps of the subpathway in this organism are:
    1. Multifunctional 2-oxoglutarate metabolism enzyme (kgd)
    2. no protein annotated in this organism
    This subpathway is part of the pathway tricarboxylic acid cycle, which is itself part of Carbohydrate metabolism.
    View all proteins of this organism that are known to be involved in the subpathway that synthesizes succinate from 2-oxoglutarate (transferase route), the pathway tricarboxylic acid cycle and in Carbohydrate metabolism.

    Pathwayi: tricarboxylic acid cycle

    This protein is involved in step 1 of the subpathway that synthesizes succinyl-CoA from 2-oxoglutarate (dehydrogenase route).1 Publication
    Proteins known to be involved in this subpathway in this organism are:
    1. Multifunctional 2-oxoglutarate metabolism enzyme (kgd)
    This subpathway is part of the pathway tricarboxylic acid cycle, which is itself part of Carbohydrate metabolism.
    View all proteins of this organism that are known to be involved in the subpathway that synthesizes succinyl-CoA from 2-oxoglutarate (dehydrogenase route), the pathway tricarboxylic acid cycle and in Carbohydrate metabolism.

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Active sitei314Proton acceptor; for succinyltransferase activityBy similarity1
    Binding sitei5792-oxoglutarate1
    Binding sitei6042-oxoglutarate1
    Metal bindingi645Magnesium1
    Metal bindingi678Magnesium1
    Metal bindingi680Magnesium; via carbonyl oxygen1
    Binding sitei952Thiamine pyrophosphate1
    Binding sitei10202-oxoglutarate1
    Binding sitei1038Allosteric activator1
    Binding sitei1054Allosteric activator1
    Binding sitei1142Allosteric activator1

    GO - Molecular functioni

    GO - Biological processi

    Keywordsi

    Molecular functionAcyltransferase, Allosteric enzyme, Decarboxylase, Lyase, Multifunctional enzyme, Oxidoreductase, Transferase
    Biological processTricarboxylic acid cycle
    LigandMagnesium, Metal-binding, Thiamine pyrophosphate

    Enzyme and pathway databases

    BioCyciMSME246196:G1H7P-5022-MONOMER
    BRENDAi4.1.1.71 3512
    UniPathwayiUPA00223; UER00997
    UPA00223; UER01001

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Multifunctional 2-oxoglutarate metabolism enzyme
    Alternative name(s):
    2-hydroxy-3-oxoadipate synthase (EC:2.2.1.5)
    Short name:
    HOA synthase
    Short name:
    HOAS
    2-oxoglutarate carboxy-lyase
    2-oxoglutarate decarboxylase
    Alpha-ketoglutarate decarboxylase (EC:4.1.1.71)
    Short name:
    KG decarboxylase
    Short name:
    KGD
    Alpha-ketoglutarate-glyoxylate carboligase
    Including the following 2 domains:
    2-oxoglutarate dehydrogenase E1 component (EC:1.2.4.2)
    Short name:
    ODH E1 component
    Alternative name(s):
    Alpha-ketoglutarate dehydrogenase E1 component
    Short name:
    KDH E1 component
    Dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex (EC:2.3.1.61)
    Alternative name(s):
    2-oxoglutarate dehydrogenase complex E2 component
    Short name:
    ODH E2 component
    Short name:
    OGDC-E2
    Dihydrolipoamide succinyltransferase
    Gene namesi
    Name:kgd
    Synonyms:sucA
    Ordered Locus Names:MSMEG_5049, MSMEI_4922
    OrganismiMycobacterium smegmatis (strain ATCC 700084 / mc(2)155)
    Taxonomic identifieri246196 [NCBI]
    Taxonomic lineageiBacteriaActinobacteriaCorynebacterialesMycobacteriaceaeMycobacteriumMycobacterium fortuitum complex
    Proteomesi

    Pathology & Biotechi

    Disruption phenotypei

    Cells lacking this gene do not show any ODH activity, in contrast to wild-type, demonstrating that this protein is part of a functional ODH complex in mycobacteria.1 Publication

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi539H → A: Loss of KG decarboxylase activity. 1 Publication1
    Mutagenesisi579H → A: Loss of KG decarboxylase activity. 1 Publication1
    Mutagenesisi747H → A: 40-fold decrease in KG decarboxylase activity. 1 Publication1
    Mutagenesisi781R → A: Increase in KG decarboxylase activity. 1 Publication1
    Mutagenesisi1020H → A: Loss of KG decarboxylase activity. 1 Publication1
    Mutagenesisi1034E → A: Loss of activation by acetyl-CoA. 1 Publication1
    Mutagenesisi1062R → A: Loss of activation by acetyl-CoA. 1 Publication1

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00003107181 – 1227Multifunctional 2-oxoglutarate metabolism enzymeAdd BLAST1227

    Proteomic databases

    PRIDEiA0R2B1

    Interactioni

    Subunit structurei

    Homodimer. Interacts with the FHA domain of unphosphorylated GarA. The 2-oxoglutarate dehydrogenase (ODH) complex contains multiple copies of three enzymatic components: 2-oxoglutarate dehydrogenase (E1), dihydrolipoamide succinyltransferase (E2) and lipoamide dehydrogenase (E3).2 Publications

    Protein-protein interaction databases

    IntActiA0R2B1, 1 interactor
    STRINGi246196.MSMEG_5049

    Structurei

    Secondary structure

    11227
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Beta strandi124 – 132Combined sources9
    Helixi134 – 149Combined sources16
    Helixi157 – 171Combined sources15
    Helixi173 – 176Combined sources4
    Beta strandi178 – 189Combined sources12
    Beta strandi196 – 199Combined sources4
    Beta strandi213 – 216Combined sources4
    Helixi219 – 221Combined sources3
    Helixi224 – 238Combined sources15
    Turni239 – 241Combined sources3
    Helixi245 – 247Combined sources3
    Beta strandi252 – 256Combined sources5
    Beta strandi275 – 280Combined sources6
    Helixi294 – 300Combined sources7
    Beta strandi305 – 313Combined sources9
    Turni314 – 316Combined sources3
    Helixi319 – 332Combined sources14
    Helixi336 – 345Combined sources10
    Helixi367 – 380Combined sources14
    Helixi381 – 383Combined sources3
    Helixi395 – 398Combined sources4
    Turni401 – 403Combined sources3
    Helixi406 – 408Combined sources3
    Helixi412 – 414Combined sources3
    Beta strandi416 – 419Combined sources4
    Beta strandi429 – 431Combined sources3
    Helixi432 – 443Combined sources12
    Beta strandi444 – 450Combined sources7
    Helixi457 – 467Combined sources11
    Helixi476 – 499Combined sources24
    Beta strandi500 – 502Combined sources3
    Helixi504 – 506Combined sources3
    Helixi514 – 527Combined sources14
    Beta strandi531 – 536Combined sources6
    Helixi542 – 548Combined sources7
    Helixi554 – 557Combined sources4
    Turni558 – 560Combined sources3
    Helixi567 – 570Combined sources4
    Beta strandi571 – 573Combined sources3
    Helixi576 – 578Combined sources3
    Beta strandi582 – 587Combined sources6
    Beta strandi589 – 592Combined sources4
    Beta strandi594 – 599Combined sources6
    Turni606 – 609Combined sources4
    Helixi610 – 624Combined sources15
    Beta strandi630 – 632Combined sources3
    Beta strandi637 – 644Combined sources8
    Helixi645 – 650Combined sources6
    Helixi652 – 658Combined sources7
    Turni659 – 662Combined sources4
    Turni664 – 666Combined sources3
    Beta strandi672 – 677Combined sources6
    Helixi686 – 689Combined sources4
    Beta strandi691 – 694Combined sources4
    Helixi697 – 702Combined sources6
    Beta strandi706 – 710Combined sources5
    Helixi714 – 731Combined sources18
    Beta strandi735 – 740Combined sources6
    Helixi753 – 755Combined sources3
    Helixi758 – 764Combined sources7
    Helixi770 – 780Combined sources11
    Helixi786 – 812Combined sources27
    Helixi822 – 824Combined sources3
    Helixi837 – 846Combined sources10
    Turni858 – 860Combined sources3
    Helixi861 – 873Combined sources13
    Helixi878 – 891Combined sources14
    Beta strandi895 – 900Combined sources6
    Turni901 – 905Combined sources5
    Beta strandi913 – 916Combined sources4
    Turni918 – 920Combined sources3
    Helixi926 – 931Combined sources6
    Beta strandi942 – 947Combined sources6
    Helixi953 – 965Combined sources13
    Beta strandi969 – 974Combined sources6
    Helixi978 – 984Combined sources7
    Helixi985 – 990Combined sources6
    Turni991 – 994Combined sources4
    Helixi995 – 999Combined sources5
    Beta strandi1006 – 1010Combined sources5
    Beta strandi1014 – 1016Combined sources3
    Helixi1025 – 1031Combined sources7
    Beta strandi1034 – 1036Combined sources3
    Beta strandi1038 – 1040Combined sources3
    Helixi1045 – 1057Combined sources13
    Beta strandi1064 – 1068Combined sources5
    Helixi1071 – 1074Combined sources4
    Beta strandi1076 – 1078Combined sources3
    Helixi1082 – 1086Combined sources5
    Beta strandi1092 – 1094Combined sources3
    Helixi1097 – 1100Combined sources4
    Helixi1106 – 1108Combined sources3
    Beta strandi1111 – 1115Combined sources5
    Helixi1119 – 1130Combined sources12
    Beta strandi1135 – 1140Combined sources6
    Beta strandi1142 – 1145Combined sources4
    Helixi1148 – 1156Combined sources9
    Beta strandi1163 – 1171Combined sources9
    Beta strandi1174 – 1176Combined sources3
    Helixi1177 – 1187Combined sources11
    Helixi1189 – 1192Combined sources4
    Beta strandi1196 – 1200Combined sources5
    Beta strandi1204 – 1207Combined sources4
    Helixi1211 – 1225Combined sources15

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    2XT6X-ray2.74A/B116-1227[»]
    2XT9X-ray2.20A361-1227[»]
    2XTAX-ray2.20A/B/C/D361-1227[»]
    2Y0PX-ray2.40A/B/C/D361-1227[»]
    2YICX-ray1.96A/B/C/D361-1227[»]
    2YIDX-ray2.25A/B/C/D361-1227[»]
    3ZHQX-ray2.50A/B/C/D361-1227[»]
    3ZHRX-ray2.10A/B/C/D361-1227[»]
    3ZHSX-ray2.10A/B/C/D361-1227[»]
    3ZHTX-ray2.15A/B/C/D361-1227[»]
    3ZHUX-ray2.30A/B/C/D361-1227[»]
    3ZHVX-ray2.30A/B/C/D361-1227[»]
    ProteinModelPortaliA0R2B1
    SMRiA0R2B1
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiA0R2B1

    Family & Domainsi

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni1 – 412-oxoglutarate dehydrogenase E1, N-terminal partAdd BLAST41
    Regioni42 – 88LinkerAdd BLAST47
    Regioni89 – 335Succinyltransferase E2Add BLAST247
    Regioni336 – 12272-oxoglutarate dehydrogenase E1, C-terminal partAdd BLAST892
    Regioni539 – 540Thiamine pyrophosphate binding2
    Regioni604 – 606Thiamine pyrophosphate binding3
    Regioni645 – 647Thiamine pyrophosphate binding3
    Regioni1089 – 1092Allosteric activator4
    Regioni1149 – 1150Allosteric activator2

    Coiled coil

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Coiled coili783 – 814Sequence analysisAdd BLAST32

    Domaini

    Is a fusion protein with two major domains exhibiting structural features of an E1 and E2 protein, and a short sequence stretch of E1 localized at the N-terminus, which is connected by a linker region to the rest of the protein.By similarity

    Sequence similaritiesi

    Keywords - Domaini

    Coiled coil

    Phylogenomic databases

    eggNOGiENOG4105C7P Bacteria
    COG0508 LUCA
    COG0567 LUCA
    HOGENOMiHOG000259587
    KOiK01616
    OMAiIDMVCYR
    OrthoDBiPOG091H03SK

    Family and domain databases

    Gene3Di3.30.559.10, 1 hit
    InterProiView protein in InterPro
    IPR001078 2-oxoacid_DH_actylTfrase
    IPR032106 2-oxogl_dehyd_N
    IPR011603 2oxoglutarate_DH_E1
    IPR023213 CAT-like_dom_sf
    IPR001017 DH_E1
    IPR031717 KGD_C
    IPR029061 THDP-binding
    IPR005475 Transketolase-like_Pyr-bd
    PANTHERiPTHR23152 PTHR23152, 1 hit
    PfamiView protein in Pfam
    PF00198 2-oxoacid_dh, 1 hit
    PF16078 2-oxogl_dehyd_N, 1 hit
    PF00676 E1_dh, 1 hit
    PF16870 OxoGdeHyase_C, 1 hit
    PF02779 Transket_pyr, 1 hit
    PIRSFiPIRSF000157 Oxoglu_dh_E1, 1 hit
    SMARTiView protein in SMART
    SM00861 Transket_pyr, 1 hit
    SUPFAMiSSF52518 SSF52518, 2 hits
    TIGRFAMsiTIGR00239 2oxo_dh_E1, 1 hit

    Sequencei

    Sequence statusi: Complete.

    A0R2B1-1 [UniParc]FASTAAdd to basket

    « Hide

            10         20         30         40         50
    MSSSPSPFGQ NEWLVEEMYR KFRDDPSSVD PSWHEFLVDY SPEPTTDSAS
    60 70 80 90 100
    NGRTTTAAPV TPPTPAPAPA PEPKAAPKPA AKTEAKPAKP AKSATPAKGD
    110 120 130 140 150
    ESQILRGAAA AVVKNMNASL EVPTATSVRA IPAKLMIDNR VVINNHLKRT
    160 170 180 190 200
    RGGKISFTHL LGYAIVQAVK KFPNMNRHFA VVDGKPTAIT PAHTNLGLAI
    210 220 230 240 250
    DLQGKDGNRS LVVAAIKRCE TMRFGQFIAA YEDIVRRARD GKLTAEDFSG
    260 270 280 290 300
    VTISLTNPGT LGTVHSVPRL MQGQGAIIGA GAMEYPAEFQ GASEERIADL
    310 320 330 340 350
    GIGKLITLTS TYDHRIIQGA ESGDFLRTIH QLLLDDDFFD EIFRELGIPY
    360 370 380 390 400
    EPVRWRTDNP DSIEDKNARV IELIAAYRNR GHLMADIDPL RLDNTRFRSH
    410 420 430 440 450
    PDLDVNSHGL TLWDLDREFK VDGFAGVQRK KLRDILSVLR DAYCRHVGVE
    460 470 480 490 500
    YTHILEPEQQ RWIQERVETK HDKPTVAEQK YILSKLNAAE AFETFLQTKY
    510 520 530 540 550
    VGQKRFSLEG AETVIPMMDA VIDQCAEHGL DEVVIAMPHR GRLNVLANIV
    560 570 580 590 600
    GKPYSQIFSE FEGNLNPSQA HGSGDVKYHL GATGTYIQMF GDNDIEVSLT
    610 620 630 640 650
    ANPSHLEAVD PVLEGLVRAK QDLLDTGEEG SDNRFSVVPL MLHGDAAFAG
    660 670 680 690 700
    QGVVAETLNL ALLRGYRTGG TIHIVVNNQI GFTTAPTDSR SSEYCTDVAK
    710 720 730 740 750
    MIGAPIFHVN GDDPEACAWV ARLAVDFRQA FKKDVVIDML CYRRRGHNEG
    760 770 780 790 800
    DDPSMTQPYM YDVIDTKRGS RKAYTEALIG RGDISMKEAE DALRDYQGQL
    810 820 830 840 850
    ERVFNEVREL EKHEIEPSES VEADQQIPSK LATAVDKAML QRIGDAHLAL
    860 870 880 890 900
    PEGFTVHPRV RPVLEKRREM AYEGRIDWAF AELLALGSLI AEGKLVRLSG
    910 920 930 940 950
    QDTQRGTFTQ RHAVIVDRKT GEEFTPLQLL ATNPDGTPTG GKFLVYNSAL
    960 970 980 990 1000
    SEFAAVGFEY GYSVGNPDAM VLWEAQFGDF VNGAQSIIDE FISSGEAKWG
    1010 1020 1030 1040 1050
    QLSDVVLLLP HGHEGQGPDH TSGRIERFLQ LWAEGSMTIA MPSTPANYFH
    1060 1070 1080 1090 1100
    LLRRHGKDGI QRPLIVFTPK SMLRNKAAVS DIRDFTESKF RSVLEEPMYT
    1110 1120 1130 1140 1150
    DGEGDRNKVT RLLLTSGKIY YELAARKAKE NREDVAIVRI EQLAPLPRRR
    1160 1170 1180 1190 1200
    LAETLDRYPN VKEKFWVQEE PANQGAWPSF GLTLPEILPD HFTGLKRISR
    1210 1220
    RAMSAPSSGS SKVHAVEQQE ILDTAFG
    Length:1,227
    Mass (Da):135,944
    Last modified:January 9, 2007 - v1
    Checksum:i76C5BFFD1638A391
    GO

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    CP000480 Genomic DNA Translation: ABK74238.1
    CP001663 Genomic DNA Translation: AFP41366.1
    RefSeqiWP_011730279.1, NZ_CP009494.1
    YP_889299.1, NC_008596.1

    Genome annotation databases

    EnsemblBacteriaiABK74238; ABK74238; MSMEG_5049
    AFP41366; AFP41366; MSMEI_4922
    GeneIDi4535402
    KEGGimsb:LJ00_24970
    msg:MSMEI_4922
    msm:MSMEG_5049
    PATRICifig|246196.19.peg.4927

    Entry informationi

    Entry nameiKGD_MYCS2
    AccessioniPrimary (citable) accession number: A0R2B1
    Secondary accession number(s): I7GDF5
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 13, 2007
    Last sequence update: January 9, 2007
    Last modified: May 23, 2018
    This is version 87 of the entry and version 1 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programProkaryotic Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. PATHWAY comments
      Index of metabolic and biosynthesis pathways
    2. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    3. SIMILARITY comments
      Index of protein domains and families

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