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Protein

Multifunctional 2-oxoglutarate metabolism enzyme

Gene

kgd

Organism
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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, which can endow M.tuberculosis with the metabolic plasticity required for growth on diverse host-derived carbon sources. Appears to play a predominant role in growth on carbohydrates as the sole carbon source, and only a minimal role during growth on fatty acids.4 Publications

Catalytic activityi

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

Cofactori

Protein has several cofactor binding sites:

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.2 Publications

Kineticsi

  1. KM=0.48 mM for 2-oxoglutarate1 Publication
  2. KM=0.196 mM for magnesium ions1 Publication
  3. KM=0.019 mM for thiamine pyrophosphate1 Publication

    Pathwayi: tricarboxylic acid cycle

    This protein is involved in step 1 of the subpathway that synthesizes succinate from 2-oxoglutarate (transferase route).
    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).
    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 sitei316Proton acceptor; for succinyltransferase activityBy similarity1
    Binding sitei5812-oxoglutarateBy similarity1
    Binding sitei6062-oxoglutarateBy similarity1
    Metal bindingi649MagnesiumBy similarity1
    Metal bindingi682MagnesiumBy similarity1
    Metal bindingi684Magnesium; via carbonyl oxygenBy similarity1
    Binding sitei956Thiamine pyrophosphateBy similarity1
    Binding sitei10242-oxoglutarateBy similarity1
    Binding sitei1042Allosteric activatorBy similarity1
    Binding sitei1058Allosteric activatorBy similarity1
    Binding sitei1146Allosteric activatorBy similarity1

    GO - Molecular functioni

    GO - Biological processi

    • 2-oxoglutarate metabolic process Source: MTBBASE
    • growth Source: MTBBASE
    • oxidation-reduction process Source: MTBBASE
    • tricarboxylic acid cycle Source: MTBBASE

    Keywordsi

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

    Enzyme and pathway databases

    BioCyciMetaCyc:G185E-5419-MONOMER.
    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
    Ordered Locus Names:Rv1248c
    OrganismiMycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
    Taxonomic identifieri83332 [NCBI]
    Taxonomic lineageiBacteriaActinobacteriaCorynebacterialesMycobacteriaceaeMycobacteriumMycobacterium tuberculosis complex
    Proteomesi
    • UP000001584 Componenti: Chromosome

    Organism-specific databases

    TubercuListiRv1248c.

    Subcellular locationi

    GO - Cellular componenti

    • cell wall Source: MTBBASE
    • cytosol Source: GO_Central
    • oxoglutarate dehydrogenase complex Source: GO_Central
    • plasma membrane Source: MTBBASE
    • pyruvate dehydrogenase complex Source: MTBBASE

    Pathology & Biotechi

    Disruption phenotypei

    Attempts to disrupt Rv1248c in M.tuberculosis H37Rv and Erdman strains by homologous recombination were unsuccessful, raising the possibility that Rv1248c may be essential (PubMed:20416504). However, deletion mutants were readily obtained in a strain derived from H37Rv in PubMed:19936047. The mutant strain grows as well as wild-type in medium containing both carbohydrates (dextrose and glycerol) and fatty acids, under a CO2 enriched atmosphere, but shows a marked growth defect when grown in medium containing carbohydrates as the sole carbon source in the presence of CO2. Simultaneous disruption of korAB and kgd results in strict dependence upon the glyoxylate shunt for growth. Growth of the kgd mutant strain on fatty acids as the sole carbon source is similar to that of the wild type strain regardless of the presence of CO2. But cells lacking both korAB and kgd is significantly more retarded for growth on fatty acids than is either korAB or kgd deleted mutant alone.2 Publications

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00003107221 – 1231Multifunctional 2-oxoglutarate metabolism enzymeAdd BLAST1231

    Proteomic databases

    PaxDbiP9WIS5.

    Interactioni

    Subunit structurei

    Homodimer (By similarity). The 2-oxoglutarate dehydrogenase (ODH) complex contains multiple copies of three enzymatic components: 2-oxoglutarate dehydrogenase (E1), dihydrolipoamide succinyltransferase (E2) and lipoamide dehydrogenase (E3) (By similarity). Interacts with the FHA domain of unphosphorylated GarA.By similarity2 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    garAP9WJA94EBI-6405560,EBI-6405522

    Protein-protein interaction databases

    IntActiP9WIS5. 1 interactor.
    STRINGi83332.Rv1248c.

    Structurei

    3D structure databases

    ProteinModelPortaliP9WIS5.
    SMRiP9WIS5.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni1 – 412-oxoglutarate dehydrogenase E1, N-terminal partAdd BLAST41
    Regioni42 – 88LinkerAdd BLAST47
    Regioni89 – 337Succinyltransferase E2Add BLAST249
    Regioni338 – 12312-oxoglutarate dehydrogenase E1, C-terminal partAdd BLAST894
    Regioni541 – 542Thiamine pyrophosphate bindingBy similarity2
    Regioni606 – 608Thiamine pyrophosphate bindingBy similarity3
    Regioni649 – 651Thiamine pyrophosphate bindingBy similarity3
    Regioni1093 – 1096Allosteric activatorBy similarity4
    Regioni1153 – 1154Allosteric activatorBy similarity2

    Coiled coil

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Coiled coili787 – 817Sequence analysisAdd BLAST31

    Compositional bias

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Compositional biasi61 – 113Ala-richAdd BLAST53

    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.
    KOiK01616.
    OMAiIDMVCYR.
    PhylomeDBiP9WIS5.

    Family and domain databases

    InterProiView protein in InterPro
    IPR001078. 2-oxoacid_DH_actylTfrase.
    IPR032106. 2-oxogl_dehyd_N.
    IPR011603. 2oxoglutarate_DH_E1.
    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.

    P9WIS5-1 [UniParc]FASTAAdd to basket

    « Hide

            10         20         30         40         50
    MANISSPFGQ NEWLVEEMYR KFRDDPSSVD PSWHEFLVDY SPEPTSQPAA
    60 70 80 90 100
    EPTRVTSPLV AERAAAAAPQ APPKPADTAA AGNGVVAALA AKTAVPPPAE
    110 120 130 140 150
    GDEVAVLRGA AAAVVKNMSA SLEVPTATSV RAVPAKLLID NRIVINNQLK
    160 170 180 190 200
    RTRGGKISFT HLLGYALVQA VKKFPNMNRH YTEVDGKPTA VTPAHTNLGL
    210 220 230 240 250
    AIDLQGKDGK RSLVVAGIKR CETMRFAQFV TAYEDIVRRA RDGKLTTEDF
    260 270 280 290 300
    AGVTISLTNP GTIGTVHSVP RLMPGQGAII GVGAMEYPAE FQGASEERIA
    310 320 330 340 350
    ELGIGKLITL TSTYDHRIIQ GAESGDFLRT IHELLLSDGF WDEVFRELSI
    360 370 380 390 400
    PYLPVRWSTD NPDSIVDKNA RVMNLIAAYR NRGHLMADTD PLRLDKARFR
    410 420 430 440 450
    SHPDLEVLTH GLTLWDLDRV FKVDGFAGAQ YKKLRDVLGL LRDAYCRHIG
    460 470 480 490 500
    VEYAHILDPE QKEWLEQRVE TKHVKPTVAQ QKYILSKLNA AEAFETFLQT
    510 520 530 540 550
    KYVGQKRFSL EGAESVIPMM DAAIDQCAEH GLDEVVIGMP HRGRLNVLAN
    560 570 580 590 600
    IVGKPYSQIF TEFEGNLNPS QAHGSGDVKY HLGATGLYLQ MFGDNDIQVS
    610 620 630 640 650
    LTANPSHLEA VDPVLEGLVR AKQDLLDHGS IDSDGQRAFS VVPLMLHGDA
    660 670 680 690 700
    AFAGQGVVAE TLNLANLPGY RVGGTIHIIV NNQIGFTTAP EYSRSSEYCT
    710 720 730 740 750
    DVAKMIGAPI FHVNGDDPEA CVWVARLAVD FRQRFKKDVV IDMLCYRRRG
    760 770 780 790 800
    HNEGDDPSMT NPYVYDVVDT KRGARKSYTE ALIGRGDISM KEAEDALRDY
    810 820 830 840 850
    QGQLERVFNE VRELEKHGVQ PSESVESDQM IPAGLATAVD KSLLARIGDA
    860 870 880 890 900
    FLALPNGFTA HPRVQPVLEK RREMAYEGKI DWAFGELLAL GSLVAEGKLV
    910 920 930 940 950
    RLSGQDSRRG TFSQRHSVLI DRHTGEEFTP LQLLATNSDG SPTGGKFLVY
    960 970 980 990 1000
    DSPLSEYAAV GFEYGYTVGN PDAVVLWEAQ FGDFVNGAQS IIDEFISSGE
    1010 1020 1030 1040 1050
    AKWGQLSNVV LLLPHGHEGQ GPDHTSARIE RFLQLWAEGS MTIAMPSTPS
    1060 1070 1080 1090 1100
    NYFHLLRRHA LDGIQRPLIV FTPKSMLRHK AAVSEIKDFT EIKFRSVLEE
    1110 1120 1130 1140 1150
    PTYEDGIGDR NKVSRILLTS GKLYYELAAR KAKDNRNDLA IVRLEQLAPL
    1160 1170 1180 1190 1200
    PRRRLRETLD RYENVKEFFW VQEEPANQGA WPRFGLELPE LLPDKLAGIK
    1210 1220 1230
    RISRRAMSAP SSGSSKVHAV EQQEILDEAF G
    Length:1,231
    Mass (Da):135,902
    Last modified:April 16, 2014 - v1
    Checksum:i96C255612BA12889
    GO

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AL123456 Genomic DNA. Translation: CCP44004.1.
    PIRiG70953.
    RefSeqiNP_215764.2. NC_000962.3.
    WP_003898790.1. NZ_KK339370.1.

    Genome annotation databases

    EnsemblBacteriaiCCP44004; CCP44004; Rv1248c.
    GeneIDi887084.
    KEGGimtu:Rv1248c.

    Similar proteinsi

    Entry informationi

    Entry nameiKGD_MYCTU
    AccessioniPrimary (citable) accession number: P9WIS5
    Secondary accession number(s): L0T8T9, O50463, Q7D8I9
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 16, 2014
    Last sequence update: April 16, 2014
    Last modified: June 7, 2017
    This is version 24 of the entry and version 1 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programProkaryotic Protein Annotation Program

    Miscellaneousi

    Caution

    Was originally (PubMed:9634230 and PubMed:12218036) annotated as sucA because of sequence similarity, but this protein was shown (PubMed:16045627) not to be able to serve as the E1 component of 2-oxoglutarate dehydrogenase (ODH). However, it was later shown that this protein does in fact sustain ODH activity (PubMed:21867916), and requires specific activation by acetyl-CoA.2 Publications

    Keywords - Technical termi

    Allosteric enzyme, Complete proteome, Multifunctional enzyme, Reference proteome

    Documents

    1. Mycobacterium tuberculosis strains ATCC 25618 / H37Rv and CDC 1551 / Oshkosh
      Mycobacterium tuberculosis strains ATCC 25618 / H37Rv and CDC 1551 / Oshkosh: entries and gene names
    2. PATHWAY comments
      Index of metabolic and biosynthesis pathways
    3. SIMILARITY comments
      Index of protein domains and families