S3DB74 · GLOI_GLAL2

Function

function

3-isopropylmalate dehydrogenase; part of the gene cluster that mediates the biosynthesis of pneumocandins, lipohexapeptides of the echinocandin family that prevent fungal cell wall formation by non-competitive inhibition of beta-1,3-glucan synthase (PubMed:27705900).
The 10,12-dimethylmyristoyl side chain is synthesized by the reducing polyketide synthase gloL/GLPKS4 (PubMed:27494047).
The thioesterase gloN/GLHYD exclusively interacts with gloL/GLPKS4 to maintain turnover of the polyketide side chain (PubMed:27494047).
The 10R,12S-dimethylmyristic acid is then transferred to the first thiolation domain of the nonribosomal peptide synthetase gloA/GLNRPS4 by the acyl-AMP ligase gloD/GLligase, followed by its acylation to L-ornithine to trigger elongation of the cyclic hexapeptide (PubMed:27494047).
L-ornithine, 4R-hydroxyl-L-proline (generated from L-proline by the dioxygenase gloF/GLOXY2), 3S-hydroxyl-L-homotyrosine (generated by gloG/GLHtyB, gloH/GLHtyA, gloI/GLHtyC, gloJ/GLHtyD and hydroxylated at C-3 by the dioxygenase gloM/GLOXY1), 3R-hydroxyl-L-glutamine (generated from L-glutamine probably by the dioxygenase gloE/GLOXY3) and 3S-hydroxyl-L-proline (generated from L-proline by the dioxygenase gloF/GLOXY2 to yield pneumocandin B0), or 3S-hydroxyl-4S-methyl-L-proline (generated from L-leucine by the dioxygenase gloC/GLOXY4 to yield pneumocandin A0) are sequentially added to the growing chain (PubMed:25270390, PubMed:25527531, PubMed:25879325).
The last C domain of gloA/GLNRPS4 is proposed to be responsible for cyclization by condensation to form the peptide bond between L-ornithine and 3S-hydroxyl-4S-methyl-L-proline (for pneumocandin A0) or 3S-hydroxyl-L-proline (for pneumocandin B0). Finally, the subsequent C-4 hydroxylation of 3S-hydroxyl-L-homotyrosine and L-ornithine dihydroxylation at C-4 and C-5 are performed by the cytochrome P450 monooxygenases gloP/GLP450-1 and gloO/GLP450-2, respectively (PubMed:25879325).

Catalytic activity

Cofactor

Mg2+ (UniProtKB | Rhea| CHEBI:18420 )

Mn2+ (UniProtKB | Rhea| CHEBI:29035 )

Note: Binds 1 Mg2+ or Mn2+ ion per subunit.

Biotechnology

Pneumocandin B0 is the starting molecule for the first semisynthetic echinocandin antifungal drug, caspofungin acetate (PubMed:25527531).
Pneumocandin B0 is a minor fermentation product, and its industrial production was achieved by a combination of extensive mutation and medium optimization (PubMed:25527531).
Inactivation of three of gloP/GLP450-1, gloO/GLP450-2, and gloM/GLOXY1 generates 13 different pneumocandin analogs that lack one, two, three, or four hydroxyl groups on 4R,5R-dihydroxy-ornithine and 3S,4S-dihydroxy-homotyrosine of the parent hexapeptide (PubMed:25879325).
All of these cyclic lipopeptides show potent antifungal activities, and two new metabolites pneumocandins F and G are more potent in vitro against Candida species and Aspergillus fumigatus than the principal fermentation products, pneumocandins A0 and B0 (PubMed:25879325).
Moreover, feeding alternative side chain precursors yields acrophiarin and 4 additional pneumocandin congeners with straight C14, C15, and C16 side chains. One of those compounds, pneumocandin I, has elevated antifungal activity and similar hemolytic activity compared to pneumocandin B0, the starting molecule for caspofungin, demonstrating the potential for using gloD/GLligase for future engineering of new echinocandin analogs (PubMed:27494047).

Pathway

Mycotoxin biosynthesis.

Features

Showing features for binding site, site.

TypeIDPosition(s)Description
Binding site92substrate
Binding site98substrate
Binding site108substrate
Site194Critical for catalysis
Binding site228Mg2+ (UniProtKB | ChEBI)
Binding site253Mg2+ (UniProtKB | ChEBI)
Binding site257Mg2+ (UniProtKB | ChEBI)
Binding site294-300NADP+ (UniProtKB | ChEBI)
Binding site307NADP+ (UniProtKB | ChEBI)

GO annotations

AspectTerm
Cellular Componentcytosol
Molecular Function3-isopropylmalate dehydrogenase activity
Molecular Functionmagnesium ion binding
Molecular FunctionNAD binding
Biological ProcessL-leucine biosynthetic process

Keywords

Enzyme and pathway databases

Names & Taxonomy

Protein names

  • Recommended name
    3-isopropylmalate dehydrogenase gloI
  • EC number
  • Alternative names
    • L-homotyrosine biosynthesis sub-cluster protein gloI
    • Pneumocandin biosynthesis cluster protein I

Gene names

    • Name
      gloI
    • Synonyms
      GLHtyC
    • ORF names
      GLAREA_10038

Organism names

Accessions

  • Primary accession
    S3DB74

Proteomes

Subcellular Location

Phenotypes & Variants

PTM/Processing

Features

Showing features for chain.

TypeIDPosition(s)Description
ChainPRO_00004444941-3733-isopropylmalate dehydrogenase gloI

Interaction

Subunit

Homodimer.

Protein-protein interaction databases

Structure

Family & Domains

Sequence similarities

Phylogenomic databases

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Length
    373
  • Mass (Da)
    39,688
  • Last updated
    2013-09-18 v1
  • Checksum
    C53AD268B13A704E
MTKQFDIVVFPGDYGGPEVMAEGIKVLKAIERKHQSDVSFNLKYHLIGGASFDIHDTPITTEALEDAKAASAVLLGAVGGPKWDGTPVPVESGLGRLRKFLDAFGNIRPVNFIAPSLVNCSSFKEHVVSGTDITIVRELTGGIYFGARQEHDGSFNSASDLDHYDRDSIVRAARLAGKLAMSRQPHLPVTSLDKANLLAACGRLWRGVVKEVFETEFPTIKLSHMLIDTAAMNVARRPTSLNGIILTSNMFGDIISDEASAIPGSLGLLPSASLCAIPTVLDASKVRGIYEPIHGSAPDIAGQGIINPTGMILSVAMMLRYSLAMPEAADSIEAAVGKVIEDDCRTSDIGGRASTADFGDAVVIALRNCLDKN

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
KE145356
EMBL· GenBank· DDBJ
EPE34344.1
EMBL· GenBank· DDBJ
Genomic DNA

Genome annotation databases

Similar Proteins

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care. Our staff consists of biologists and biochemists that are not trained to give medical advice.
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