O50463 (KGD_MYCTU) Reviewed, UniProtKB/Swiss-Prot
Last modified
May 1, 2013.
Version 89.
History...
Names·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order
Names·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize orderNames and origin
| Protein names | Recommended name: Multifunctional 2-oxoglutarate metabolism enzyme Alternative name(s): 2-hydroxy-3-oxoadipate synthase Short name=HOA synthase Short name=HOAS EC=2.2.1.5 2-oxoglutarate carboxy-lyase 2-oxoglutarate decarboxylase Alpha-ketoglutarate decarboxylase Short name=KG decarboxylase Short name=KGD EC=4.1.1.71 Alpha-ketoglutarate-glyoxylate carboligase Including the following 2 domains:
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| Gene names |
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| Organism | Mycobacterium tuberculosis [Reference proteome] [HAMAP] | ||||
| Taxonomic identifier | 1773 [NCBI] | ||||
| Taxonomic lineage | Bacteria › Actinobacteria › Actinobacteridae › Actinomycetales › Corynebacterineae › Mycobacteriaceae › Mycobacterium › Mycobacterium tuberculosis complex![]() |
Protein attributes
| Sequence length | 1231 AA. |
| Sequence status | Complete. |
| Protein existence | Evidence at protein level |
General annotation (Comments)
| Function | 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. Ref.3 Ref.4 Ref.6 Ref.8 Ref.9 |
| Catalytic activity | 2-oxoglutarate + glyoxylate = 2-hydroxy-3-oxoadipate + CO2. Ref.8 Ref.9 2-oxoglutarate = succinate semialdehyde + CO2. Ref.8 Ref.9 2-oxoglutarate + [dihydrolipoyllysine-residue succinyltransferase] lipoyllysine = [dihydrolipoyllysine-residue succinyltransferase] S-succinyldihydrolipoyllysine + CO2. Ref.8 Ref.9 Succinyl-CoA + enzyme N(6)-(dihydrolipoyl)lysine = CoA + enzyme N(6)-(S-succinyldihydrolipoyl)lysine. Ref.8 Ref.9 |
| Cofactor | |
| Enzyme regulation | Alpha-ketoglutarate dehydrogenase and decarboxylase activities are inhibited by unphosphorylated GarA, and allosterically activated by acetyl-CoA, the main substrate of the TCA cycle. Ref.7 Ref.9 |
| Pathway | |
| Subunit structure | 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. Ref.5 Ref.7 |
| Domain | 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. |
| Disruption phenotype | Attempts to disrupt Rv1248c in M.tuberculosis H37Rv and Erdman strains by homologous recombination were unsuccessful, raising the possibility that Rv1248c may be essential (Ref.8). However, deletion mutants were readily obtained in a strain derived from H37Rv in Ref.6. 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. Ref.6 Ref.8 |
| Sequence similarities | Belongs to the 2-oxoacid dehydrogenase family. Kgd subfamily. |
| Caution | Was originally (Ref.1 and Ref.2) annotated as sucA because of sequence similarity, but this protein was shown (Ref.3) 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 (Ref.9), and requires specific activation by acetyl-CoA. |
| Biophysicochemical properties | Kinetic parameters: KM=0.48 mM for 2-oxoglutarate Ref.4 KM=0.196 mM for magnesium ions KM=0.019 mM for thiamine pyrophosphate |
| Sequence caution | The sequence CAA15904.1 differs from that shown. Reason: Erroneous initiation. |
Ontologies
Binary interactions
With | Entry | #Exp. | IntAct | Notes |
|---|---|---|---|---|
| garA | P64897 | 2 | EBI-6405560,EBI-6405522 |
Sequence annotation (Features)
| Feature key | Position(s) | Length | Description | Graphical view | Feature identifier | ||||
Molecule processing | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Chain | 1 – 1231 | 1231 | Multifunctional 2-oxoglutarate metabolism enzyme | PRO_0000310722 | |||||
Regions | |||||||||
| Region | 1 – 41 | 41 | 2-oxoglutarate dehydrogenase E1, N-terminal part | ||||||
| Region | 42 – 88 | 47 | Linker | ||||||
| Region | 89 – 337 | 249 | Succinyltransferase E2 | ||||||
| Region | 338 – 1231 | 894 | 2-oxoglutarate dehydrogenase E1, C-terminal part | ||||||
| Region | 541 – 542 | 2 | Thiamine pyrophosphate binding By similarity | ||||||
| Region | 606 – 608 | 3 | Thiamine pyrophosphate binding By similarity | ||||||
| Region | 649 – 651 | 3 | Thiamine pyrophosphate binding By similarity | ||||||
| Region | 1093 – 1096 | 4 | Allosteric activator By similarity | ||||||
| Region | 1153 – 1154 | 2 | Allosteric activator By similarity | ||||||
| Coiled coil | 787 – 817 | 31 | Potential | ||||||
| Compositional bias | 61 – 113 | 53 | Ala-rich | ||||||
Sites | |||||||||
| Active site | 316 | 1 | Proton acceptor; for succinyltransferase activity By similarity | ||||||
| Metal binding | 649 | 1 | Magnesium By similarity | ||||||
| Metal binding | 682 | 1 | Magnesium By similarity | ||||||
| Metal binding | 684 | 1 | Magnesium; via carbonyl oxygen By similarity | ||||||
| Binding site | 581 | 1 | 2-oxoglutarate By similarity | ||||||
| Binding site | 606 | 1 | 2-oxoglutarate By similarity | ||||||
| Binding site | 956 | 1 | Thiamine pyrophosphate By similarity | ||||||
| Binding site | 1024 | 1 | 2-oxoglutarate By similarity | ||||||
| Binding site | 1042 | 1 | Allosteric activator By similarity | ||||||
| Binding site | 1058 | 1 | Allosteric activator By similarity | ||||||
| Binding site | 1146 | 1 | Allosteric activator By similarity | ||||||
Sequences
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References
| « Hide 'large scale' references | |
| [1] | "Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence." Cole S.T., Brosch R., Parkhill J., Garnier T., Churcher C.M., Harris D.E., Gordon S.V., Eiglmeier K., Gas S., Barry C.E. III, Tekaia F., Badcock K., Basham D., Brown D., Chillingworth T., Connor R., Davies R.M., Devlin K. Barrell B.G.Nature 393:537-544(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. Strain: ATCC 25618 / H37Rv. |
| [2] | "Whole-genome comparison of Mycobacterium tuberculosis clinical and laboratory strains." Fleischmann R.D., Alland D., Eisen J.A., Carpenter L., White O., Peterson J.D., DeBoy R.T., Dodson R.J., Gwinn M.L., Haft D.H., Hickey E.K., Kolonay J.F., Nelson W.C., Umayam L.A., Ermolaeva M.D., Salzberg S.L., Delcher A., Utterback T.R. Fraser C.M.J. Bacteriol. 184:5479-5490(2002) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. Strain: CDC 1551 / Oshkosh. |
| [3] | "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: LACK OF FUNCTION AS A 2-OXOGLUTARATE DEHYDROGENASE COMPONENT. Strain: ATCC 25618 / H37Rv. |
| [4] | "Variant tricarboxylic acid cycle in Mycobacterium tuberculosis: identification of alpha-ketoglutarate decarboxylase." Tian J., Bryk R., Itoh M., Suematsu M., Nathan C. Proc. Natl. Acad. Sci. U.S.A. 102:10670-10675(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION AS A 2-OXOGLUTARATE DECARBOXYLASE, COFACTORS, ROLE IN A VARIANT TCA CYCLE, KINETIC PARAMETERS. Strain: ATCC 25618 / H37Rv. |
| [5] | "Regulation of glutamate metabolism by protein kinases in mycobacteria." O'Hare H.M., Duran R., Cervenansky C., Bellinzoni M., Wehenkel A.M., Pritsch O., Obal G., Baumgartner J., Vialaret J., Johnsson K., Alzari P.M. Mol. Microbiol. 70:1408-1423(2008) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH GARA. Strain: ATCC 25618 / H37Rv. |
| [6] | "An anaerobic-type alpha-ketoglutarate ferredoxin oxidoreductase completes the oxidative tricarboxylic acid cycle of Mycobacterium tuberculosis." Baughn A.D., Garforth S.J., Vilcheze C., Jacobs W.R. Jr. PLoS Pathog. 5:E1000662-E1000662(2009) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE, ROLE IN TCA CYCLE. Strain: ATCC 25618 / H37Rv. |
| [7] | "An intramolecular switch regulates phosphoindependent FHA domain interactions in Mycobacterium tuberculosis." Nott T.J., Kelly G., Stach L., Li J., Westcott S., Patel D., Hunt D.M., Howell S., Buxton R.S., O'Hare H.M., Smerdon S.J. Sci. Signal. 2:RA12-RA12(2009) [PubMed] [Europe PMC] [Abstract] Cited for: ENZYME REGULATION, INTERACTION WITH GARA. Strain: ATCC 25618 / H37Rv. |
| [8] | "Activity-based metabolomic profiling of enzymatic function: identification of Rv1248c as a mycobacterial 2-hydroxy-3-oxoadipate synthase." de Carvalho L.P., Zhao H., Dickinson C.E., Arango N.M., Lima C.D., Fischer S.M., Ouerfelli O., Nathan C., Rhee K.Y. Chem. Biol. 17:323-332(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION AS A HOA SYNTHASE, CATALYTIC ACTIVITY, COFACTORS, SUBSTRATE SPECIFICITY, DISRUPTION PHENOTYPE. Strain: ATCC 25618 / H37Rv. |
| [9] | "Functional plasticity and allosteric regulation of alpha-ketoglutarate decarboxylase in central mycobacterial metabolism." Wagner T., Bellinzoni M., Wehenkel A., O'Hare H.M., Alzari P.M. Chem. Biol. 18:1011-1020(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION AS A MULTIFUNCTIONAL ENZYME, CATALYTIC ACTIVITY, ENZYME REGULATION. Strain: ATCC 25618 / H37Rv. |
Cross-references
Sequence databases | |
|---|---|
| EMBL GenBank DDBJ | BX842576 Genomic DNA. Translation: CAA15904.1. Different initiation. AE000516 Genomic DNA. Translation: AAK45544.1. AL123456 Genomic DNA. Translation: CCP44004.1. |
| PIR | G70953. |
| RefSeq | NP_335730.1. NC_002755.2. |
3D structure databases | |
| ProteinModelPortal | O50463. |
| SMR | O50463. Positions 116-335, 367-1231. |
| ModBase | Search... |
Protein-protein interaction databases | |
| IntAct | O50463. 1 interaction. |
| STRING | 83332.Rv1248c. |
Proteomic databases | |
| PRIDE | O50463. |
Protocols and materials databases | |
| StructuralBiologyKnowledgebase | Search... |
Genome annotation databases | |
| EnsemblBacteria | AAK45544; AAK45544; MT1286. |
| GeneID | 924785. |
| KEGG | mtc:MT1286. mtu:Rv1248c. |
| PATRIC | 18124592. VBIMycTub22151_1415. |
Organism-specific databases | |
| TubercuList | Rv1248c. |
Phylogenomic databases | |
| eggNOG | COG0508. |
| HOGENOM | HOG000259587. |
| KO | K01616. |
| OMA | IIKRGGA. |
| ProtClustDB | PRK12270. |
Enzyme and pathway databases | |
| UniPathway | UPA00223; UER00997. UPA00223; UER01001. |
Family and domain databases | |
| Gene3D | 3.30.559.10. 1 hit. |
| InterPro | IPR001078. 2-oxoacid_DH_actylTfrase. IPR011603. 2oxoglutarate_DH_E1. IPR023213. CAT-like_dom. IPR001017. DH_E1. IPR005475. Transketolase-like_Pyr-bd. [Graphical view] |
| PANTHER | PTHR23152. PTHR23152. 1 hit. |
| Pfam | PF00198. 2-oxoacid_dh. 1 hit. PF00676. E1_dh. 1 hit. PF02779. Transket_pyr. 1 hit. [Graphical view] |
| PIRSF | PIRSF000157. Oxoglu_dh_E1. 1 hit. |
| SMART | SM00861. Transket_pyr. 1 hit. [Graphical view] |
| TIGRFAMs | TIGR00239. 2oxo_dh_E1. 1 hit. |
| ProtoNet | Search... |
Entry information
| Entry name | KGD_MYCTU | ||||||||
| Accession | Primary (citable) accession number: O50463 Secondary accession number(s): L0T8T9, Q7D8I9 | ||||||||
| Entry history |
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| Entry status | Reviewed (UniProtKB/Swiss-Prot) | ||||||||
| Annotation program | Prokaryotic Protein Annotation Program | ||||||||
Relevant documents
| Mycobacterium tuberculosis strains ATCC 25618 / H37Rv and CDC 1551 / Oshkosh Mycobacterium tuberculosis strains ATCC 25618 / H37Rv and CDC 1551 / Oshkosh: entries and gene names |
| PATHWAY comments Index of metabolic and biosynthesis pathways |
| SIMILARITY comments Index of protein domains and families |

Clusters with
