bims-toxgon 2026-03-22 papers

Issue of 2026–03–22
four papers selected by
Lakesh Kumar, BITS Pilani

bioRxiv. 2026 Mar 03. pii: 2026.03.02.709153. [Epub ahead of print]

Minimum inoculum of resistance assay for evaluating for anti-toxoplasmosis compounds that target phenyl alanine tRNA synthetase.

Taher Uddin, Payal Mittal, Han Xie, Bruno Melillo, Amit Sharma, Arnab K Chatterjee, L David Sibley.

Toxoplasma gondii is a globally important intracellular parasite, and treatment regimens are limited by the failure of drugs to target latent tissue cysts. Developing new candidates for treatment also needs to address the potential for resistance to arise. Here, we developed a Minimum Inoculum for Resistance (MIR) assay as a quantitative metric for evaluating inhibitors of T. gondii . The MIR assay, adapted from assays used in malaria drug discovery, measures the frequency for pre-existing resistance alleles by exposing different sized parasite populations to drug pressure. We profiled a series of bicyclic pyrrolidone analogs that inhibit phenylalanine tRNA synthetase (PheRS). We demonstrate that these inhibitors require higher inocula to lead to parasite resistance (up to > 10 8 parasites) in comparison with an inhibitor of DNA synthesis, and that MIR values vary across inhibitors with closely related chemical structures. Clonal analysis of resistant parasites emerging from MIR assays revealed both new and previously identified resistance conferring mutations in Tg PheRS, and structural modeling revealed their potential impact the enzyme active site. The MIR assay provides a functional benchmark to compare new and existing inhibitors, allowing for rational prioritization of lead compounds with a high genetic barrier to resistance.

DOI: https://doi.org/10.64898/2026.03.02.709153

Annu Rev Biochem. 2026 Mar 20.

Molecular Structure and Function of Zinc-Dependent Histone Deacetylases.

David W Christianson.

The eleven known zinc-dependent histone deacetylases (HDACs) catalyze the deacetylation or deacylation of myriad protein and small molecule substrates throughout the cell. The biological functions of HDACs are much more diverse than the name HDAC implies, but this name is nonetheless retained for historical purposes. The chemical mechanism of catalysis is generally conserved among HDAC isozymes: Electrophilic activation of the substrate is achieved by zinc coordination and hydrogen bonding, and nucleophilic activation of a zinc-bound water molecule is enhanced by a general base. Since aberrant activity is observed for specific HDAC isozymes in certain diseases, the development of isozyme-selective inhibitors is a current priority in worldwide medicinal chemistry campaigns. In this review, the biological functions and chemical mechanisms of the HDACs are discussed to establish the molecular context of catalysis and inhibition, particularly as the chemistry of catalysis is harnessed in the development of mechanism-based inhibitors.

DOI: https://doi.org/10.1146/annurev-biochem-051424-053005

Mol Biomed. 2026 Mar 20. pii: 35. [Epub ahead of print]7(1):

The JMJD family histone demethylases: structure, mechanism of action, diseases and therapeutic targets.

Yilin Hong, Hanshi Guo, Qiang Chen, Chundong Yu.

The Jumonji C domain-containing (JMJD) family of histone demethylases constitutes an essential class of epigenetic regulators that dynamically sculpt gene expression programs through the erasure of methyl groups from histone lysine and arginine residues. Dysregulation of these enzymes is increasingly implicated in the pathogenesis of a wide spectrum of human diseases. Yet, a fragmented, disease-specific understanding has thus far hindered a unified view of their functions across different pathological states. In this review, we provide a comprehensive and comparative analysis of the JMJD family, synthesizing their roles and mechanisms across diverse human conditions, including cancer, neurological disorders, inflammatory, autoimmune, cardiovascular, and metabolic diseases. We highlight that individual JMJD proteins can function paradoxically as both promoters and suppressors of pathology, a duality determined by the specific cellular and pathological context. A key novelty of our work is its integrated, cross-disease perspective, which moves beyond conventional silos to illuminate common pathophysiological pathways and unique regulatory networks orchestrated by these epigenetic erasers. Furthermore, we critically assess the associated therapeutic landscape, summarizing advances in the development of small-molecule JMJD inhibitors and discussing innovative strategies to tackle enduring challenges, such as enzymatic redundancy and selectivity. By integrating insights from disparate disease models, this review seeks to forge a holistic understanding of JMJD biology and accelerate the development of novel epigenetic therapeutics directed at this pivotal protein family.

Keywords: Disease pathogenesis; Epigenetic; Histone demethylases; JMJD family; JMJD inhibitors

DOI: https://doi.org/10.1186/s43556-026-00434-3

Nat Commun. 2026 03 20. pii: 2583. [Epub ahead of print]17(1):

A cell cycle-dependent transition of acetylation to phosphorylation regulates timely centrosome maturation.

Jimin Li, Jianqiang Liang, Guifang Chen, Xuejie Wang, Yanyan Wang, Jingfei Zhan, Yunjing Guo, Jiadong Wang, Xuefeng Chen.

Centrosomes must undergo maturation in the G2/M phases to activate the microtubule-organizing activity, ensuring proper bipolar spindle assembly and chromosome segregation. Polo-like kinase 1(PLK1) is crucial for centrosome maturation. How the cell cycle controls timely PLK1 recruitment and centrosome maturation remains elusive. Here, we find that the ubiquitin E3 ligase RNF40 localizes to centrosomes and is phosphorylated by CDK1 on T529/T557 in the G2/M phases. This phosphorylation primes its binding to PLK1 and promotes timely PLK1 recruitment and centrosome maturation, establishing the CDK1-RNF40-PLK1 cascade as a mechanism controlling centrosome maturation. We also find that RNF40 is acetylated in interphase and undergoes an acetylation-to-phosphorylation transition in late G2 and M phases, which permits timely activation of the CDK1-RNF40-PLK1 cascade. Constitutive RNF40 acetylation or deficient RNF40 phosphorylation impairs PLK1 localization, microtubule nucleation, and bipolar spindle assembly, causing mitotic catastrophe. Thus, the cell cycle-dependent transition of RNF40 modifications ensures timely centrosome maturation and chromosome segregation.

DOI: https://doi.org/10.1038/s41467-026-70271-z