The crystal structure of mouse IRG1 suggests that cis-aconitate decarboxylase has an open and closed conformation

Chun, Hye Lin; Lee, So Yeon; Kim, Ki-Hwa; Lee, Chang Sup; Oh, Tae‐Jin; Park, Hyun Ho

doi:10.1371/journal.pone.0242383

Cited by 6 publications

(4 citation statements)

References 32 publications

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“…The sulfur atom of Met154 is located at 4.1 Å distance from the Phe381 ring centre (dashed yellow line) at an angle of 68° to the plane of the aromatic ring. The Ile154 residue of the aligned mACOD1 structure of Chun et al 9 (PDB ID code 7BR9) is shown in purple. …”

Section: Resultsmentioning

confidence: 99%

“…The mechanism of ACOD1 catalysis includes an opening of the active site by tilting the smaller domain relative to the larger domain (Fig. 1 ) 8 , 9 . The side chains of residues 152 and 154 are located at the interface of the smaller and larger domain, and residue 154 also lines a hydrophobic pocket in the active centre.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanism of ACOD1 catalysis includes an opening of the active site by tilting the smaller domain relative to the larger domain (Fig. 1 ) 8 , 9 . This opening is required for the substrate to get to the active site.…”

Section: Introductionmentioning

confidence: 99%

“…It is expected that the enzyme’s activity is determined not only by the conserved active site residues interacting with the substrate, but also by residues involved in the opening and closing movements. To determine the structural basis for the difference in ACOD1 activity between mice and human, we investigated residues near the active site and at the domain interface that might be relevant for the higher activity of mouse ACOD1 (mACOD1) 8 , 9 .

Figure 1 Crystal structure of a subunit of the human ACOD1 homodimer (PDB ID code 6R6U) 8 .…”

Section: Introductionmentioning

confidence: 99%

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Amino acid positions near the active site determine the reduced activity of human ACOD1 compared to murine ACOD1

Chen

Yalcin

Zhao

et al. 2023

Sci Rep

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Abstractcis-Aconitate decarboxylase (ACOD1, IRG1) converts cis-aconitate to the immunomodulatory and antibacterial metabolite itaconate. Although the active site residues of human and mouse ACOD1 are identical, the mouse enzyme is about fivefold more active. Aiming to identify the cause of this difference, we mutated positions near the active site in human ACOD1 to the corresponding residues of mouse ACOD1 and measured resulting activities in vitro and in transfected cells. Interestingly, Homosapiens is the only species with methionine instead of isoleucine at residue 154 and introduction of isoleucine at this position increased the activity of human ACOD1 1.5-fold in transfected cells and 3.5-fold in vitro. Enzyme activity of gorilla ACOD1, which is almost identical to the human enzyme but has isoleucine at residue 154, was similar to the mouse enzyme in vitro. Met154 in human ACOD1 forms a sulfur-π bond to Phe381, which is positioned to impede access of the substrate to the active site. It appears that the ACOD1 sequence has changed at position 154 during human evolution, resulting in a pronounced decrease in activity. This change might have offered a selective advantage in diseases such as cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%