UniProtKB - P9WHH9 (DLDH_MYCTU)
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Protein
Dihydrolipoyl dehydrogenase
Gene
lpdC
Organism
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Status
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
- KM=66 µM for NAD+2 Publications
- KM=7.3 µM for NADH2 Publications
- KM=110 µM for thio-NADH2 Publications
- KM=16 mM for D,L-lipoamide2 Publications
- 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 key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Binding sitei | 50 | FAD2 Publications | 1 | |
Binding sitei | 113 | FAD; via amide nitrogen and carbonyl oxygenBy similarity | 1 | |
Binding sitei | 201 | NADBy similarity | 1 | |
Binding sitei | 309 | FAD2 Publications | 1 | |
Binding sitei | 317 | FAD; via amide nitrogen2 Publications | 1 | |
Active sitei | 443 | Proton acceptorBy similarity | 1 |
Regions
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Nucleotide bindingi | 33 – 41 | FAD2 Publications | 9 | |
Nucleotide bindingi | 178 – 182 | NADBy similarity | 5 | |
Nucleotide bindingi | 266 – 269 | NADBy similarity | 4 |
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
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
Keywordsi
Molecular function | Antioxidant, Oxidoreductase |
Biological process | Glycolysis, Tricarboxylic acid cycle, Virulence |
Ligand | FAD, Flavoprotein, NAD |
Enzyme and pathway databases
Reactomei | R-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 |
Organismi | Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) |
Taxonomic identifieri | 83332 [NCBI] |
Taxonomic lineagei | Bacteria › Actinobacteria › Corynebacteriales › Mycobacteriaceae › Mycobacterium › Mycobacterium tuberculosis complex › |
Proteomesi |
|
Organism-specific databases
TubercuListi | Rv0462. |
Subcellular locationi
- Cytoplasm Curated
GO - Cellular componenti
- cytosol Source: MTBBASE
- extracellular region Source: MTBBASE
- plasma membrane Source: MTBBASE
- pyruvate dehydrogenase complex Source: MTBBASE
Keywords - Cellular componenti
CytoplasmPathology & 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 key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Mutagenesisi | 5 | D → A: Reduces lipoamide dehydrogenase activity by 95%. 1 Publication | 1 | |
Mutagenesisi | 43 | N → A: Reduces lipoamide dehydrogenase activity by 89%. 1 Publication | 1 | |
Mutagenesisi | 93 | R → A: Reduces lipoamide dehydrogenase activity by 94%. 1 Publication | 1 | |
Mutagenesisi | 93 | R → E: Reduces lipoamide dehydrogenase activity by 96%. 1 Publication | 1 | |
Mutagenesisi | 103 | K → E: Reduces lipoamide dehydrogenase activity by 82%. 1 Publication | 1 | |
Mutagenesisi | 386 | H → K: Reduces lipoamide dehydrogenase activity by 91%. 1 Publication | 1 | |
Mutagenesisi | 464 | F → A: Reduces lipoamide dehydrogenase activity by 95%. 1 Publication | 1 |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000068034 | 1 – 464 | Dihydrolipoyl dehydrogenaseAdd BLAST | 464 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Disulfide bondi | 41 ↔ 46 | Redox-active1 Publication |
Keywords - PTMi
Disulfide bondProteomic databases
PaxDbi | P9WHH9. |
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
Protein-protein interaction databases
STRINGi | 83332.Rv0462. |
Chemistry databases
BindingDBi | P9WHH9. |
Structurei
Secondary structure
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more detailsFeature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Beta strandi | 2 – 9 | Combined sources | 8 | |
Helixi | 13 – 24 | Combined sources | 12 | |
Beta strandi | 29 – 32 | Combined sources | 4 | |
Helixi | 39 – 44 | Combined sources | 6 | |
Helixi | 46 – 65 | Combined sources | 20 | |
Turni | 66 – 70 | Combined sources | 5 | |
Beta strandi | 71 – 73 | Combined sources | 3 | |
Helixi | 79 – 103 | Combined sources | 25 | |
Beta strandi | 107 – 109 | Combined sources | 3 | |
Beta strandi | 111 – 125 | Combined sources | 15 | |
Beta strandi | 131 – 140 | Combined sources | 10 | |
Beta strandi | 144 – 146 | Combined sources | 3 | |
Helixi | 161 – 165 | Combined sources | 5 | |
Beta strandi | 172 – 177 | Combined sources | 6 | |
Helixi | 181 – 192 | Combined sources | 12 | |
Beta strandi | 196 – 200 | Combined sources | 5 | |
Beta strandi | 202 – 207 | Combined sources | 6 | |
Helixi | 212 – 225 | Combined sources | 14 | |
Beta strandi | 228 – 230 | Combined sources | 3 | |
Beta strandi | 234 – 240 | Combined sources | 7 | |
Beta strandi | 245 – 253 | Combined sources | 9 | |
Beta strandi | 255 – 265 | Combined sources | 11 | |
Beta strandi | 269 – 271 | Combined sources | 3 | |
Beta strandi | 274 – 276 | Combined sources | 3 | |
Helixi | 278 – 281 | Combined sources | 4 | |
Beta strandi | 289 – 291 | Combined sources | 3 | |
Beta strandi | 304 – 306 | Combined sources | 3 | |
Helixi | 308 – 311 | Combined sources | 4 | |
Helixi | 317 – 332 | Combined sources | 16 | |
Helixi | 342 – 344 | Combined sources | 3 | |
Beta strandi | 347 – 349 | Combined sources | 3 | |
Beta strandi | 351 – 359 | Combined sources | 9 | |
Helixi | 362 – 367 | Combined sources | 6 | |
Beta strandi | 372 – 378 | Combined sources | 7 | |
Helixi | 379 – 381 | Combined sources | 3 | |
Helixi | 383 – 388 | Combined sources | 6 | |
Beta strandi | 394 – 400 | Combined sources | 7 | |
Turni | 401 – 404 | Combined sources | 4 | |
Beta strandi | 405 – 413 | Combined sources | 9 | |
Helixi | 416 – 419 | Combined sources | 4 | |
Helixi | 420 – 428 | Combined sources | 9 | |
Helixi | 433 – 436 | Combined sources | 4 | |
Helixi | 448 – 458 | Combined sources | 11 |
3D structure databases
Select the link destinations: PDBei RCSB PDBi PDBji Links Updated | PDB entry | Method | Resolution (Å) | Chain | Positions | PDBsum |
2A8X | X-ray | 2.40 | A/B | 1-464 | [»] | |
3II4 | X-ray | 2.42 | A/B | 1-464 | [»] | |
4M52 | X-ray | 2.40 | A/B/C/D | 1-464 | [»] | |
ProteinModelPortali | P9WHH9. | |||||
SMRi | P9WHH9. | |||||
ModBasei | Search... | |||||
MobiDBi | Search... |
Family & Domainsi
Sequence similaritiesi
Belongs to the class-I pyridine nucleotide-disulfide oxidoreductase family.Curated
Keywords - Domaini
Redox-active centerPhylogenomic databases
eggNOGi | ENOG4107QN2. Bacteria. COG1249. LUCA. |
KOi | K00382. |
OMAi | TMSEAVM. |
PhylomeDBi | P9WHH9. |
Family and domain databases
Gene3Di | 3.30.390.30. 1 hit. 3.50.50.60. 3 hits. |
InterProi | View 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. |
Pfami | View protein in Pfam PF07992. Pyr_redox_2. 1 hit. PF02852. Pyr_redox_dim. 1 hit. |
PIRSFi | PIRSF000350. Mercury_reductase_MerA. 1 hit. |
SUPFAMi | SSF51905. SSF51905. 1 hit. SSF55424. SSF55424. 1 hit. |
TIGRFAMsi | TIGR01350. lipoamide_DH. 1 hit. |
PROSITEi | View protein in PROSITE PS00076. PYRIDINE_REDOX_1. 1 hit. |
i Sequence
Sequence statusi: Complete.
P9WHH9-1 [UniParc]FASTAAdd to basket
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
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | AL123456 Genomic DNA. Translation: CCP43195.1. |
PIRi | B70828. |
RefSeqi | NP_214976.1. NC_000962.3. WP_003402301.1. NZ_KK339370.1. |
Genome annotation databases
EnsemblBacteriai | CCP43195; CCP43195; Rv0462. |
GeneIDi | 886300. |
KEGGi | mtu:Rv0462. |
Similar proteinsi
Entry informationi
Entry namei | DLDH_MYCTU | |
Accessioni | P9WHH9Primary (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: | February 28, 2018 | |
This is version 31 of the entry and version 1 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Prokaryotic Protein Annotation Program |