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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)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei50 – 501FAD2 Publications
    Binding sitei113 – 1131FAD; via amide nitrogen and carbonyl oxygenBy similarity
    Binding sitei201 – 2011NADBy similarity
    Binding sitei309 – 3091FAD2 Publications
    Binding sitei317 – 3171FAD; via amide nitrogen2 Publications
    Active sitei443 – 4431Proton acceptorBy similarity

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi33 – 419FAD2 Publications
    Nucleotide bindingi178 – 1825NADBy similarity
    Nucleotide bindingi266 – 2694NADBy similarity

    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

    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)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi5 – 51D → A: Reduces lipoamide dehydrogenase activity by 95%. 1 Publication
    Mutagenesisi43 – 431N → A: Reduces lipoamide dehydrogenase activity by 89%. 1 Publication
    Mutagenesisi93 – 931R → A: Reduces lipoamide dehydrogenase activity by 94%. 1 Publication
    Mutagenesisi93 – 931R → E: Reduces lipoamide dehydrogenase activity by 96%. 1 Publication
    Mutagenesisi103 – 1031K → E: Reduces lipoamide dehydrogenase activity by 82%. 1 Publication
    Mutagenesisi386 – 3861H → K: Reduces lipoamide dehydrogenase activity by 91%. 1 Publication
    Mutagenesisi464 – 4641F → A: Reduces lipoamide dehydrogenase activity by 95%. 1 Publication

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 464464Dihydrolipoyl dehydrogenasePRO_0000068034Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    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

    1
    464
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi2 – 98Combined sources
    Helixi13 – 2412Combined sources
    Beta strandi29 – 324Combined sources
    Helixi39 – 446Combined sources
    Helixi46 – 6520Combined sources
    Turni66 – 705Combined sources
    Beta strandi71 – 733Combined sources
    Helixi79 – 10325Combined sources
    Beta strandi107 – 1093Combined sources
    Beta strandi111 – 12515Combined sources
    Beta strandi131 – 14010Combined sources
    Beta strandi144 – 1463Combined sources
    Helixi161 – 1655Combined sources
    Beta strandi172 – 1776Combined sources
    Helixi181 – 19212Combined sources
    Beta strandi196 – 2005Combined sources
    Beta strandi202 – 2076Combined sources
    Helixi212 – 22514Combined sources
    Beta strandi228 – 2303Combined sources
    Beta strandi234 – 2407Combined sources
    Beta strandi245 – 2539Combined sources
    Beta strandi255 – 26511Combined sources
    Beta strandi269 – 2713Combined sources
    Beta strandi274 – 2763Combined sources
    Helixi278 – 2814Combined sources
    Beta strandi289 – 2913Combined sources
    Beta strandi304 – 3063Combined sources
    Helixi308 – 3114Combined sources
    Helixi317 – 33216Combined sources
    Helixi342 – 3443Combined sources
    Beta strandi347 – 3493Combined sources
    Beta strandi351 – 3599Combined sources
    Helixi362 – 3676Combined sources
    Beta strandi372 – 3787Combined sources
    Helixi379 – 3813Combined sources
    Helixi383 – 3886Combined sources
    Beta strandi394 – 4007Combined sources
    Turni401 – 4044Combined sources
    Beta strandi405 – 4139Combined sources
    Helixi416 – 4194Combined sources
    Helixi420 – 4289Combined sources
    Helixi433 – 4364Combined sources
    Helixi448 – 45811Combined sources

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    2A8XX-ray2.40A/B1-464[»]
    3II4X-ray2.42A/B1-464[»]
    4M52X-ray2.40A/B/C/D1-464[»]
    ProteinModelPortaliP9WHH9.
    SMRiP9WHH9. Positions 1-464.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Sequence similaritiesi

    Keywords - Domaini

    Redox-active center

    Phylogenomic databases

    eggNOGiENOG4107QN2. Bacteria.
    COG1249. LUCA.
    KOiK00382.
    OMAiVEVMPTI.
    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
    EntryMethodResolution (Å)ChainPositionsPDBsum
    2A8XX-ray2.40A/B1-464[»]
    3II4X-ray2.42A/B1-464[»]
    4M52X-ray2.40A/B/C/D1-464[»]
    ProteinModelPortaliP9WHH9.
    SMRiP9WHH9. Positions 1-464.
    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.
    OMAiVEVMPTI.
    PhylomeDBiP9WHH9.

    Enzyme and pathway databases

    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...

    Publicationsi

    « Hide 'large scale' publications
    1. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
      Strain: ATCC 25618 / H37Rv.
    2. "Mycobacterium tuberculosis lipoamide dehydrogenase is encoded by Rv0462 and not by the lpdA or lpdB genes."
      Argyrou A., Blanchard J.S.
      Biochemistry 40:11353-11363(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, CATALYTIC ACTIVITY, SUBSTRATE SPECIFICITY, KINETIC PARAMETERS, COFACTOR, GENE NAME, SUBUNIT, REACTION MECHANISM.
      Strain: ATCC 25618 / H37Rv.
    3. "Metabolic enzymes of mycobacteria linked to antioxidant defense by a thioredoxin-like protein."
      Bryk R., Lima C.D., Erdjument-Bromage H., Tempst P., Nathan C.
      Science 295:1073-1077(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION AS AN ANTIOXIDANT, SUBUNIT.
      Strain: ATCC 25618 / H37Rv.
    4. "Mycobacterium tuberculosis appears to lack alpha-ketoglutarate dehydrogenase and encodes pyruvate dehydrogenase in widely separated genes."
      Tian J., Bryk R., Shi S., Erdjument-Bromage H., Tempst P., Nathan C.
      Mol. Microbiol. 57:859-868(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION AS A PDH COMPONENT, BIOPHYSICOCHEMICAL PROPERTIES, IDENTIFICATION IN THE PDH COMPLEX.
      Strain: ATCC 25618 / H37Rv.
    5. "Virulence of Mycobacterium tuberculosis depends on lipoamide dehydrogenase, a member of three multienzyme complexes."
      Venugopal A., Bryk R., Shi S., Rhee K., Rath P., Schnappinger D., Ehrt S., Nathan C.
      Cell Host Microbe 9:21-31(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION AS A BCKADH COMPONENT, ROLE IN VIRULENCE, DISRUPTION PHENOTYPE, IDENTIFICATION IN THE BCKADH COMPLEX.
      Strain: ATCC 25618 / H37Rv.
    6. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Strain: ATCC 25618 / H37Rv.
    7. "Crystal structure and functional analysis of lipoamide dehydrogenase from Mycobacterium tuberculosis."
      Rajashankar K.R., Bryk R., Kniewel R., Buglino J.A., Nathan C.F., Lima C.D.
      J. Biol. Chem. 280:33977-33983(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) IN COMPLEX WITH FAD, DISULFIDE BOND, SUBUNIT, FUNCTION, MUTAGENESIS OF ASP-5; ASN-43; ARG-93; LYS-103; HIS-386 AND PHE-464.
    8. "Triazaspirodimethoxybenzoyls as selective inhibitors of mycobacterial lipoamide dehydrogenase."
      Bryk R., Arango N., Venugopal A., Warren J.D., Park Y.H., Patel M.S., Lima C.D., Nathan C.
      Biochemistry 49:1616-1627(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.42 ANGSTROMS) IN COMPLEX WITH INHIBITOR AND FAD, ENZYME REGULATION, INHIBITORS.
      Strain: ATCC 25618 / H37Rv.

    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: June 8, 2016
    This is version 19 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.