Heterogeneous multimeric structure of isocitrate lyase in complex with succinate and itaconate provides novel insights into its inhibitory mechanism

Kwon, Sunghoon; Chun, Hye Lin; Ha, Hyekyung; Lee, So Yeon; Park, Hyun Ho

doi:10.1371/journal.pone.0251067

Cited by 9 publications

(3 citation statements)

References 32 publications

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“…Acyl-CoA (ACX) is the first enzyme involved in the β-oxidation of fatty acids in peroxisomes in plants . Its purpose is to degrade fatty acids to acetyl-CoA, the substrate of the glyoxylate cycle and an alternative pathway to the TCA cycle. , ICL is involved in the decarboxylation steps of the TCA cycle to produce succinate. The increase of ICL has been previously observed in other plants in response to alkaline stress in tolerant grape hybrids and in Chinese fir roots under P deficiency .…”

Section: Discussionmentioning

confidence: 99%

Unraveling the Mechanisms of Efficient Phosphorus Utilization in Popcorn (Zea mays L. var. everta): Insights from Proteomic and Metabolite Analysis

Barboza Bispo,

Teixeira do Amaral,

Pinto

et al. 2024

J. Proteome Res.

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The expansion of agriculture and the need for sustainable practices drives breeders to develop plant varieties better adapted to abiotic stress such as nutrient deficiency, which negatively impacts yields. Phosphorus (P) is crucial for photosynthesis and plant growth, but its availability in the soil is often limited, hampering crop development. In this study, we examined the response of two popcorn inbred lines, L80 and P7, which have been characterized previously as P-use inefficient and P-use efficient, respectively, under low (stress) and high P (control) availability. Physiological measurements, proteomic analysis, and metabolite assays were performed to unravel the physiological and molecular responses associated with the efficient use of P in popcorn. We observed significant differences in protein abundances in response to the P supply between the two inbred lines. A total of 421 differentially expressed proteins (DEPs) were observed in L80 and 436 DEPs in P7. These proteins were involved in photosynthesis, protein biosynthesis, biosynthesis of secondary metabolites, and energy metabolism. In addition, flavonoids accumulated in higher abundance in P7. Our results help us understand the major components of P utilization in popcorn, providing new insights for popcorn molecular breeding programs.

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Section: Discussionmentioning

confidence: 99%

Unraveling the Mechanisms of Efficient Phosphorus Utilization in Popcorn (Zea mays L. var. everta): Insights from Proteomic and Metabolite Analysis

Barboza Bispo,

Teixeira do Amaral,

Pinto

et al. 2024

J. Proteome Res.

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“…To avoid the two decarboxylation stages of the tricarboxylic acid (TCA) cycle, isocitrate lyases (ICLs; isoforms 1 and 2) catalyze the reversible conversion of isocitrate to glyoxylate and succinate in the glyoxylate cycle [ 78 ]. The previously unexplored genome of B. suis has marked the identification of ICL as one of the key findings of the study.…”

Section: Discussionmentioning

confidence: 99%

Integrated Bioinformatics-Based Subtractive Genomics Approach to Decipher the Therapeutic Drug Target and Its Possible Intervention against Brucellosis

et al. 2022

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Brucella suis, one of the causative agents of brucellosis, is Gram-negative intracellular bacteria that may be found all over the globe and it is a significant facultative zoonotic pathogen found in livestock. It may adapt to a phagocytic environment, reproduce, and develop resistance to harmful environments inside host cells, which is a crucial part of the Brucella life cycle making it a worldwide menace. The molecular underpinnings of Brucella pathogenicity have been substantially elucidated due to comprehensive methods such as proteomics. Therefore, we aim to explore the complete Brucella suis proteome to prioritize the novel proteins as drug targets via subtractive proteo-genomics analysis, an effort to conjecture the existence of distinct pathways in the development of brucellosis. Consequently, 38 unique metabolic pathways having 503 proteins were observed while among these 503 proteins, the non-homologs (n = 421), essential (n = 350), drug-like (n = 114), virulence (n = 45), resistance (n = 42), and unique to pathogen proteins were retrieved from Brucella suis. The applied subsequent hierarchical shortlisting resulted in a protein, i.e., isocitrate lyase, that may act as potential drug target, which was finalized after the extensive literature survey. The interacting partners for these shortlisted drug targets were identified through the STRING database. Moreover, structure-based studies were also performed on isocitrate lyase to further analyze its function. For that purpose, ~18,000 ZINC compounds were screened to identify new potent drug candidates against isocitrate lyase for brucellosis. It resulted in the shortlisting of six compounds, i.e., ZINC95543764, ZINC02688148, ZINC20115475, ZINC04232055, ZINC04231816, and ZINC04259566 that potentially inhibit isocitrate lyase. However, the ADMET profiling showed that all compounds fulfill ADMET properties except for ZINC20115475 showing positive Ames activity; whereas, ZINC02688148, ZINC04259566, ZINC04232055, and ZINC04231816 showed hepatoxicity while all compounds were observed to have no skin sensitization. In light of these parameters, we recommend ZINC95543764 compound for further experimental studies. According to the present research, which uses subtractive genomics, proteins that might serve as therapeutic targets and potential lead options for eradicating brucellosis have been narrowed down.

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“…For this purpose, the 3D structures of Mtb ICL1 in the apo form (PDB: 1F61) and in complex with the inhibitors 3-bromopyruvate (1), 3-nitropropionate (2), and itaconate (3) (Figure 1) were studied by means of X-ray diffraction (XRD). In the host, 3 is synthesized by decarbonylation of cis-aconitate upon activation of immune cells [6]. Despite the enzyme acts as a tetramer, it is also stable in solution as a dimer.…”

Section: Isocitrate Lyase 1 (Icl1)mentioning

confidence: 99%

An Outline of the Latest Crystallographic Studies on Inhibitor-Enzyme Complexes for the Design and Development of New Therapeutics against Tuberculosis

et al. 2021

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The elucidation of the structure of enzymes and their complexes with ligands continues to provide invaluable insights for the development of drugs against many diseases, including bacterial infections. After nearly three decades since the World Health Organization’s (WHO) declaration of tuberculosis (TB) as a global health emergency, Mycobacterium tuberculosis (Mtb) continues to claim millions of lives, remaining among the leading causes of death worldwide. In the last years, several efforts have been devoted to shortening and improving treatment outcomes, and to overcoming the increasing resistance phenomenon. The structural elucidation of enzyme-ligand complexes is fundamental to identify hot-spots, define possible interaction sites, and elaborate strategies to develop optimized molecules with high affinity. This review offers a critical and comprehensive overview of the most recent structural information on traditional and emerging mycobacterial enzymatic targets. A selection of more than twenty enzymes is here discussed, with a special emphasis on the analysis of their binding sites, the definition of the structure–activity relationships (SARs) of their inhibitors, and the study of their main intermolecular interactions. This work corroborates the potential of structural studies, substantiating their relevance in future anti-mycobacterial drug discovery and development efforts.

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Heterogeneous multimeric structure of isocitrate lyase in complex with succinate and itaconate provides novel insights into its inhibitory mechanism

Cited by 9 publications

References 32 publications

Unraveling the Mechanisms of Efficient Phosphorus Utilization in Popcorn (Zea mays L. var. everta): Insights from Proteomic and Metabolite Analysis

Unraveling the Mechanisms of Efficient Phosphorus Utilization in Popcorn (Zea mays L. var. everta): Insights from Proteomic and Metabolite Analysis

Integrated Bioinformatics-Based Subtractive Genomics Approach to Decipher the Therapeutic Drug Target and Its Possible Intervention against Brucellosis

An Outline of the Latest Crystallographic Studies on Inhibitor-Enzyme Complexes for the Design and Development of New Therapeutics against Tuberculosis

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