Human ARMT1 structure and substrate specificity indicates that it is a DUF89 family damage-control phosphatase

Dennis, Taylor N.; Kenjić, Nikola; Kang, Amrik S.; Lowenson, Jonathan D.; Kirkwood, Jay S.; Clarke, Steven; Perry, J. Jefferson P.

doi:10.1016/j.jsb.2020.107576

Cited by 3 publications

(2 citation statements)

References 29 publications

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“…The SET domain is conserved in class II and III methyltransferases (Katz et al, 2003). Like LCMT-1, both chains of ARMT1 contain a Rossman fold catalytic domain characteristic of class I methyltransferases (Katz et al, 2003;Dennis et al, 2020). Protein-ligand interactions between the SET domain of MLL5 and Compound 2, the SET domain of MLL5 and SAM, both chains of ARMT1 and Compound 2, and both chains of ARMT1 and SAM were modelled with SwissDock software (Grosdidier et al, 2011).…”

Section: Molecular Modelingmentioning

confidence: 99%

A small molecule inhibitor of leucine carboxyl methyltransferase-1 inhibits cancer cell survival

Arosarena,

Saribas,

Papadopoulos

2024

Front. Drug Discov.

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Reversible phosphorylation is the basis for signal transduction in eukaryotic cells, and this is tightly controlled by the complex interplay of kinases and phosphatases. Many malignancies are characterized by dysregulation of the delicate protein phosphorylation balance. The targeting of protein phosphatases has been gaining attention as their role in cancer development and progression has been elucidated. The protein phosphatase-2A (PP2A) family of phosphatases are the primary cellular serine/threonine phosphatases. PP2A heterotrimers containing the B55α (PR55α) regulatory subunit have been associated with oncogenic signaling, and B55 subunits are found exclusively in forms of PP2A in which the carboxyl terminus of the catalytic subunit (PP2Ac) is methylated. Methylation of PP2Ac is primarily mediated by leucine carboxyl methyltransferase-1 (LCMT-1). Demethylation is controlled by an esterase, PP2A methylesterase (PME-1). We tested two potential LCMT-1 small molecule inhibitors and found that methyl 4-methyl-2-[(2-methylbenzoyl)amino]-5-[[(3-methylphenyl)amino]carbonyl]-3-thiophenecarboxylate (henceforth referred to as Compound 2) significantly inhibited PP2Ac methylation in vitro (p = 0.0024), and in the MDA-MB-231 breast carcinoma (p = 0.0431) and Rosi melanoma (p = 0.0335) cell lines. Compound 2 significantly reduced survival in HEK-293, HS-5, MDA-MB-231 and Rosi cells; and constrained clonogenic colony formation in MCF7, MDA-MB-231 and Rosi cells. The LCMT-1inhibitor induced G0/G1 cell cycle arrest in Rosi cells (p = 0.0193) and induced apoptosis in MDA-MB-231 cells (p < 0.0001). Increased phosphorylation of the receptor-interacting serine/threonine protein kinase-1 (RIPK1) was detected in MDA-MB-231 (p = 0.0273) and Rosi cells (p = 0.0179) in response to treatment with Compound 2. These data add to the body of evidence pointing to LCMT-1 as an oncogenic target.

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Section: Molecular Modelingmentioning

confidence: 99%

A small molecule inhibitor of leucine carboxyl methyltransferase-1 inhibits cancer cell survival

Arosarena,

Saribas,

Papadopoulos

2024

Front. Drug Discov.

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“…The S. cerevisiae DUF89 protein Ymr027w showed highest activity on fructose-1-phosphate, a glycating agent and non-canonical metabolite in yeast that accumulated in YMR027W deletion strains . An in vitro phosphatase screen against an array of phosphoesters with ARMT1, the human homolog of Ymr027w [ 60 ], also showed highest activity with fructose-1-phosphate, but deficient cell models were not analyzed in this study for further validations . Other members of the DUF89 family, including human PANK4 , hydrolyze non-canonical oxidized forms of 4′-phosphopantetheine [ 59 ].…”

Section: Metabolite Repair Enzyme Discoverymentioning

confidence: 99%

Approaches for completing metabolic networks through metabolite damage and repair discovery

Griffith

Walvekar

Linster

2021

Current Opinion in Systems Biology

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Metabolites are prone to damage, either via enzymatic side reactions, which collectively form the underground metabolism, or via spontaneous chemical reactions. The resulting non-canonical metabolites that can be toxic, are mended by dedicated “metabolite repair enzymes.” Deficiencies in the latter can cause severe disease in humans, whereas inclusion of repair enzymes in metabolically engineered systems can improve the production yield of value-added chemicals. The metabolite damage and repair loops are typically not yet included in metabolic reconstructions and it is likely that many remain to be discovered. Here, we review strategies and associated challenges for unveiling non-canonical metabolites and metabolite repair enzymes, including systematic approaches based on high-resolution mass spectrometry, metabolome-wide side-activity prediction, as well as high-throughput substrate and phenotypic screens.

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Fission yeast Duf89 and Duf8901 are cobalt/nickel-dependent phosphatase–pyrophosphatases that act via a covalent aspartyl–phosphate intermediate

Sánchez

Jacewicz

Shuman

2022

Journal of Biological Chemistry

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Human ARMT1 structure and substrate specificity indicates that it is a DUF89 family damage-control phosphatase

Cited by 3 publications

References 29 publications

A small molecule inhibitor of leucine carboxyl methyltransferase-1 inhibits cancer cell survival

A small molecule inhibitor of leucine carboxyl methyltransferase-1 inhibits cancer cell survival

Approaches for completing metabolic networks through metabolite damage and repair discovery

Fission yeast Duf89 and Duf8901 are cobalt/nickel-dependent phosphatase–pyrophosphatases that act via a covalent aspartyl–phosphate intermediate

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