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Protein

Dihydrolipoyl dehydrogenase

Gene

lpdC

Organism
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Lipoamide dehydrogenase is an essential component of the alpha-ketoacid dehydrogenase complexes, namely the pyruvate dehydrogenase (PDH) complex, the branched-chain alpha-ketoacid dehydrogenase (BCKADH) complex, and likely also the 2-oxoglutarate dehydrogenase (ODH) complex. Catalyzes the reoxidation of dihydrolipoyl groups which are covalently attached to the lipoate acyltransferase components (E2) of the complexes. Is also able to catalyze the transhydrogenation of NADH and thio-NAD+ in the absence of D,L-lipoamide, and the NADH-dependent reduction of quinones in vitro.
Together with AhpC, AhpD and DlaT, Lpd constitutes an NADH-dependent peroxidase active against hydrogen and alkyl peroxides as well as serving as a peroxynitrite reductase, thus protecting the bacterium against reactive nitrogen intermediates and oxidative stress generated by the host immune system.
Appears to be essential for Mtb pathogenesis.

Catalytic activityi

Protein N(6)-(dihydrolipoyl)lysine + NAD+ = protein N(6)-(lipoyl)lysine + NADH.1 Publication

Cofactori

FAD1 PublicationNote: Binds 1 FAD per subunit.1 Publication

Enzyme regulationi

Triazaspirodimethoxybenzoyls are high-nanomolar inhibitors of M.tuberculosis Lpd and are non-competitive versus NADH, NAD+, and lipoamide and >100-fold selective compared to human Lpd.1 Publication

Kineticsi

  1. KM=66 µM for NAD+2 Publications
  2. KM=7.3 µM for NADH2 Publications
  3. KM=110 µM for thio-NADH2 Publications
  4. KM=16 mM for D,L-lipoamide2 Publications
  5. KM=120 mM for D,L-lipoate2 Publications

    pH dependencei

    Optimum pH is 8.0 for PDH complex activity. Half-maximal activity is observed at pH 7.0 and pH 9.0. Activity is abolished at pH < 5.1 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Binding sitei50FAD2 Publications1
    Binding sitei113FAD; via amide nitrogen and carbonyl oxygenBy similarity1
    Binding sitei201NADBy similarity1
    Binding sitei309FAD2 Publications1
    Binding sitei317FAD; via amide nitrogen2 Publications1
    Active sitei443Proton acceptorBy similarity1

    Regions

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Nucleotide bindingi33 – 41FAD2 Publications9
    Nucleotide bindingi178 – 182NADBy similarity5
    Nucleotide bindingi266 – 269NADBy similarity4

    GO - Molecular functioni

    • antioxidant activity Source: UniProtKB-KW
    • dihydrolipoyl dehydrogenase activity Source: MTBBASE
    • disulfide oxidoreductase activity Source: MTBBASE
    • flavin adenine dinucleotide binding Source: MTBBASE
    • NADH binding Source: MTBBASE
    • oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor Source: MTBBASE

    GO - Biological processi

    • cell redox homeostasis Source: MTBBASE
    • glycolytic process Source: UniProtKB-KW
    • growth Source: MTBBASE
    • oxidation-reduction process Source: MTBBASE
    • pathogenesis Source: UniProtKB-KW
    • tricarboxylic acid cycle Source: UniProtKB-KW
    Complete GO annotation...

    Keywords - Molecular functioni

    Antioxidant, Oxidoreductase

    Keywords - Biological processi

    Glycolysis, Tricarboxylic acid cycle, Virulence

    Keywords - Ligandi

    FAD, Flavoprotein, NAD

    Enzyme and pathway databases

    BioCyciMTBH37RV:G185E-4589-MONOMER.
    ReactomeiR-HSA-1222541. Cell redox homeostasis.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Dihydrolipoyl dehydrogenase (EC:1.8.1.4)
    Short name:
    LPD
    Alternative name(s):
    Component of peroxynitrite reductase/peroxidase complex
    Short name:
    Component of PNR/P
    Dihydrolipoamide dehydrogenase
    E3 component of alpha-ketoacid dehydrogenase complexes
    Gene namesi
    Name:lpdC
    Synonyms:lpd
    Ordered Locus Names:Rv0462
    ORF Names:MTV038.06
    OrganismiMycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
    Taxonomic identifieri83332 [NCBI]
    Taxonomic lineageiBacteriaActinobacteriaCorynebacterialesMycobacteriaceaeMycobacteriumMycobacterium tuberculosis complex
    Proteomesi
    • UP000001584 Componenti: Chromosome

    Organism-specific databases

    TubercuListiRv0462.

    Subcellular locationi

    GO - Cellular componenti

    • cytosol Source: MTBBASE
    • extracellular region Source: MTBBASE
    • plasma membrane Source: MTBBASE
    • pyruvate dehydrogenase complex Source: MTBBASE
    Complete GO annotation...

    Keywords - Cellular componenti

    Cytoplasm

    Pathology & Biotechi

    Disruption phenotypei

    Cells lacking this gene grow, albeit poorly, in standard medium with dextrose, glycerol, and fatty acids as carbon sources, but fail to grow on carbohydrates. They are less resistant than wild-type to exposition to mildly acidified nitrite, but are more resistant to oxidative stress in the form of H2O2 in vitro. Lpd-deficient strains are severely attenuated in wild-type and immunodeficient mice. In contrast to wild-type or DlaT lacking strains, strains lacking Lpd are unable to grow on leucine or isoleucine. Disruption of this gene also leads to extraordinary accumulations of pyruvate and branched chain amino and keto acids.1 Publication

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi5D → A: Reduces lipoamide dehydrogenase activity by 95%. 1 Publication1
    Mutagenesisi43N → A: Reduces lipoamide dehydrogenase activity by 89%. 1 Publication1
    Mutagenesisi93R → A: Reduces lipoamide dehydrogenase activity by 94%. 1 Publication1
    Mutagenesisi93R → E: Reduces lipoamide dehydrogenase activity by 96%. 1 Publication1
    Mutagenesisi103K → E: Reduces lipoamide dehydrogenase activity by 82%. 1 Publication1
    Mutagenesisi386H → K: Reduces lipoamide dehydrogenase activity by 91%. 1 Publication1
    Mutagenesisi464F → A: Reduces lipoamide dehydrogenase activity by 95%. 1 Publication1

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00000680341 – 464Dihydrolipoyl dehydrogenaseAdd BLAST464

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Disulfide bondi41 ↔ 46Redox-active1 Publication

    Keywords - PTMi

    Disulfide bond

    Proteomic databases

    PaxDbiP9WHH9.

    Interactioni

    Subunit structurei

    Homodimer. Identified in a complex with AhpC, AhpD and DlaT. Also is part of the PDH complex, consisting of multiple copies of AceE (E1), DlaT (E2) and Lpd (E3), and of the BCKADH complex, consisting of multiple copies of BkdA/BkdB (E1), BkdC (E2) and Lpd (E3).6 Publications

    Protein-protein interaction databases

    STRINGi83332.Rv0462.

    Structurei

    Secondary structure

    1464
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Beta strandi2 – 9Combined sources8
    Helixi13 – 24Combined sources12
    Beta strandi29 – 32Combined sources4
    Helixi39 – 44Combined sources6
    Helixi46 – 65Combined sources20
    Turni66 – 70Combined sources5
    Beta strandi71 – 73Combined sources3
    Helixi79 – 103Combined sources25
    Beta strandi107 – 109Combined sources3
    Beta strandi111 – 125Combined sources15
    Beta strandi131 – 140Combined sources10
    Beta strandi144 – 146Combined sources3
    Helixi161 – 165Combined sources5
    Beta strandi172 – 177Combined sources6
    Helixi181 – 192Combined sources12
    Beta strandi196 – 200Combined sources5
    Beta strandi202 – 207Combined sources6
    Helixi212 – 225Combined sources14
    Beta strandi228 – 230Combined sources3
    Beta strandi234 – 240Combined sources7
    Beta strandi245 – 253Combined sources9
    Beta strandi255 – 265Combined sources11
    Beta strandi269 – 271Combined sources3
    Beta strandi274 – 276Combined sources3
    Helixi278 – 281Combined sources4
    Beta strandi289 – 291Combined sources3
    Beta strandi304 – 306Combined sources3
    Helixi308 – 311Combined sources4
    Helixi317 – 332Combined sources16
    Helixi342 – 344Combined sources3
    Beta strandi347 – 349Combined sources3
    Beta strandi351 – 359Combined sources9
    Helixi362 – 367Combined sources6
    Beta strandi372 – 378Combined sources7
    Helixi379 – 381Combined sources3
    Helixi383 – 388Combined sources6
    Beta strandi394 – 400Combined sources7
    Turni401 – 404Combined sources4
    Beta strandi405 – 413Combined sources9
    Helixi416 – 419Combined sources4
    Helixi420 – 428Combined sources9
    Helixi433 – 436Combined sources4
    Helixi448 – 458Combined sources11

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    2A8XX-ray2.40A/B1-464[»]
    3II4X-ray2.42A/B1-464[»]
    4M52X-ray2.40A/B/C/D1-464[»]
    ProteinModelPortaliP9WHH9.
    SMRiP9WHH9.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Sequence similaritiesi

    Keywords - Domaini

    Redox-active center

    Phylogenomic databases

    eggNOGiENOG4107QN2. Bacteria.
    COG1249. LUCA.
    KOiK00382.
    OMAiYFEALKP.
    PhylomeDBiP9WHH9.

    Family and domain databases

    Gene3Di3.30.390.30. 1 hit.
    3.50.50.60. 2 hits.
    InterProiIPR023753. FAD/NAD-binding_dom.
    IPR016156. FAD/NAD-linked_Rdtase_dimer.
    IPR006258. Lipoamide_DH.
    IPR004099. Pyr_nucl-diS_OxRdtase_dimer.
    IPR012999. Pyr_OxRdtase_I_AS.
    [Graphical view]
    PfamiPF07992. Pyr_redox_2. 1 hit.
    PF02852. Pyr_redox_dim. 1 hit.
    [Graphical view]
    SUPFAMiSSF51905. SSF51905. 1 hit.
    SSF55424. SSF55424. 1 hit.
    TIGRFAMsiTIGR01350. lipoamide_DH. 1 hit.
    PROSITEiPS00076. PYRIDINE_REDOX_1. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    P9WHH9-1 [UniParc]FASTAAdd to basket

    « Hide

            10         20         30         40         50
    MTHYDVVVLG AGPGGYVAAI RAAQLGLSTA IVEPKYWGGV CLNVGCIPSK
    60 70 80 90 100
    ALLRNAELVH IFTKDAKAFG ISGEVTFDYG IAYDRSRKVA EGRVAGVHFL
    110 120 130 140 150
    MKKNKITEIH GYGTFADANT LLVDLNDGGT ESVTFDNAII ATGSSTRLVP
    160 170 180 190 200
    GTSLSANVVT YEEQILSREL PKSIIIAGAG AIGMEFGYVL KNYGVDVTIV
    210 220 230 240 250
    EFLPRALPNE DADVSKEIEK QFKKLGVTIL TATKVESIAD GGSQVTVTVT
    260 270 280 290 300
    KDGVAQELKA EKVLQAIGFA PNVEGYGLDK AGVALTDRKA IGVDDYMRTN
    310 320 330 340 350
    VGHIYAIGDV NGLLQLAHVA EAQGVVAAET IAGAETLTLG DHRMLPRATF
    360 370 380 390 400
    CQPNVASFGL TEQQARNEGY DVVVAKFPFT ANAKAHGVGD PSGFVKLVAD
    410 420 430 440 450
    AKHGELLGGH LVGHDVAELL PELTLAQRWD LTASELARNV HTHPTMSEAL
    460
    QECFHGLVGH MINF
    Length:464
    Mass (Da):49,239
    Last modified:April 16, 2014 - v1
    Checksum:iDD93D95DC6F76B22
    GO

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AL123456 Genomic DNA. Translation: CCP43195.1.
    PIRiB70828.
    RefSeqiNP_214976.1. NC_000962.3.
    WP_003402301.1. NZ_KK339370.1.

    Genome annotation databases

    EnsemblBacteriaiCCP43195; CCP43195; Rv0462.
    GeneIDi886300.
    KEGGimtu:Rv0462.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AL123456 Genomic DNA. Translation: CCP43195.1.
    PIRiB70828.
    RefSeqiNP_214976.1. NC_000962.3.
    WP_003402301.1. NZ_KK339370.1.

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    2A8XX-ray2.40A/B1-464[»]
    3II4X-ray2.42A/B1-464[»]
    4M52X-ray2.40A/B/C/D1-464[»]
    ProteinModelPortaliP9WHH9.
    SMRiP9WHH9.
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    STRINGi83332.Rv0462.

    Proteomic databases

    PaxDbiP9WHH9.

    Protocols and materials databases

    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsemblBacteriaiCCP43195; CCP43195; Rv0462.
    GeneIDi886300.
    KEGGimtu:Rv0462.

    Organism-specific databases

    TubercuListiRv0462.

    Phylogenomic databases

    eggNOGiENOG4107QN2. Bacteria.
    COG1249. LUCA.
    KOiK00382.
    OMAiYFEALKP.
    PhylomeDBiP9WHH9.

    Enzyme and pathway databases

    BioCyciMTBH37RV:G185E-4589-MONOMER.
    ReactomeiR-HSA-1222541. Cell redox homeostasis.

    Family and domain databases

    Gene3Di3.30.390.30. 1 hit.
    3.50.50.60. 2 hits.
    InterProiIPR023753. FAD/NAD-binding_dom.
    IPR016156. FAD/NAD-linked_Rdtase_dimer.
    IPR006258. Lipoamide_DH.
    IPR004099. Pyr_nucl-diS_OxRdtase_dimer.
    IPR012999. Pyr_OxRdtase_I_AS.
    [Graphical view]
    PfamiPF07992. Pyr_redox_2. 1 hit.
    PF02852. Pyr_redox_dim. 1 hit.
    [Graphical view]
    SUPFAMiSSF51905. SSF51905. 1 hit.
    SSF55424. SSF55424. 1 hit.
    TIGRFAMsiTIGR01350. lipoamide_DH. 1 hit.
    PROSITEiPS00076. PYRIDINE_REDOX_1. 1 hit.
    [Graphical view]
    ProtoNetiSearch...

    Entry informationi

    Entry nameiDLDH_MYCTU
    AccessioniPrimary (citable) accession number: P9WHH9
    Secondary accession number(s): L0T3N4, O53747, P66004
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: April 16, 2014
    Last sequence update: April 16, 2014
    Last modified: November 2, 2016
    This is version 21 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programProkaryotic Protein Annotation Program

    Miscellaneousi

    Miscellaneous

    The active site is a redox-active disulfide bond.

    Keywords - Technical termi

    3D-structure, Complete proteome, 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. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    3. SIMILARITY comments
      Index of protein domains and families

    Similar proteinsi

    Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
    100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
    90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
    50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.