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UniProtKB - P9WHH9 (DLDH_MYCTU)

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Protein

Dihydrolipoyl dehydrogenase

Gene

lpdC

Organism
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Status
Reviewed-Annotation score: -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.

Miscellaneous

The active site is a redox-active disulfide bond.

Catalytic activityi

Protein N6-(dihydrolipoyl)lysine + NAD+ = protein N6-(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
    • electron transfer activity Source: InterPro
    • 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
    • zymogen binding Source: CAFA
    View the complete GO annotation on QuickGO ...

    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
    View the complete GO annotation on QuickGO ...

    Keywordsi

    Molecular functionAntioxidant, Oxidoreductase
    Biological processGlycolysis, Tricarboxylic acid cycle, Virulence
    LigandFAD, 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 lineageiBacteria › Actinobacteria › Corynebacteriales › Mycobacteriaceae › Mycobacterium › Mycobacterium 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
    View the complete GO annotation on QuickGO ...

    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

    GO - Molecular functioni

    • zymogen binding Source: CAFA
    View the complete GO annotation on QuickGO ...

    Protein-protein interaction databases

    STRINGi83332.Rv0462.

    Chemistry databases

    BindingDBiP9WHH9.

    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

    Belongs to the class-I pyridine nucleotide-disulfide oxidoreductase family.Curated

    Keywords - Domaini

    Redox-active center

    Phylogenomic databases

    eggNOGiENOG4107QN2. Bacteria.
    COG1249. LUCA.
    KOiK00382.
    OMAiTMSEAVM.
    PhylomeDBiP9WHH9.

    Family and domain databases

    Gene3Di3.30.390.30. 1 hit.
    3.50.50.60. 3 hits.
    InterProiView protein in InterPro
    IPR036188. FAD/NAD-bd_sf.
    IPR023753. FAD/NAD-binding_dom.
    IPR016156. FAD/NAD-linked_Rdtase_dimer_sf.
    IPR006258. Lipoamide_DH.
    IPR001100. Pyr_nuc-diS_OxRdtase.
    IPR004099. Pyr_nucl-diS_OxRdtase_dimer.
    IPR012999. Pyr_OxRdtase_I_AS.
    PfamiView protein in Pfam
    PF07992. Pyr_redox_2. 1 hit.
    PF02852. Pyr_redox_dim. 1 hit.
    PIRSFiPIRSF000350. Mercury_reductase_MerA. 1 hit.
    SUPFAMiSSF51905. SSF51905. 1 hit.
    SSF55424. SSF55424. 1 hit.
    TIGRFAMsiTIGR01350. lipoamide_DH. 1 hit.
    PROSITEiView protein in PROSITE
    PS00076. PYRIDINE_REDOX_1. 1 hit.

    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.

    Similar proteinsi

    Entry informationi

    Entry nameiDLDH_MYCTU
    AccessioniPrimary (citable) accession number: P9WHH9
    Secondary accession number(s): L0T3N4, O53747, P66004
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 16, 2014
    Last sequence update: April 16, 2014
    Last modified: February 28, 2018
    This is version 31 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