Inhibitors of an AdoMet-dependent 3-amino-3-carboxypropyl transferase and their use as ligands for protein affinity chromatography

Protein arginine N-methyltransferases (PRMTs) selectively replace N-H for N-CH(3) at substrate protein guanidines, a post-translational modification important for a range of biological processes, such as epigenetic regulation, signal transduction and cancer progression. Selective chemical probes are required to establish the dynamic function of individual PRMTs. Herein, model inhibitors designed to occupy PRMT binding sites for an arginine substrate and S-adenosylmethionine (AdoMet) co-factor are described. Expedient access to such compounds by modular synthesis is detailed. Remarkably, biological evaluation revealed some compounds to be potent inhibitors of PRMT1, but inactive against CARM1. Docking studies show how prototype compounds may occupy the binding sites for a co-factor and arginine substrate. Overlay of PRMT1 and CARM1 binding sites suggest a difference in a single amino acid that may be responsible for the observed selectivity.

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“…5¢-Amino-5¢-deoxy-2¢,3¢-O,O-(1-methylethylidene)adenosine 8 32 (1.2 mol eq.) and aldehyde 5, 33 6 34 or 7 35 (1.0 mol eq.)…”

Section: General Procedures For First Reductive Amination: Methodsmentioning

confidence: 99%

“…Reductive alkylation of acetonide-protected 5¢-amino-5¢deoxyadenosine 8 32 with aldehyde 5, derived from aspartic acid, 33 gave the AzoAdoHcy 9 in good yield (Scheme 2). 30 Compounds bearing tert-butyl butyrate 10, or N-boc propylamine 11, side chains were made from aldehydes 6 34 and 7 35 respectively.…”

Section: Chemistrymentioning

confidence: 99%

Small molecule inhibitors that discriminate between protein arginine N-methyltransferases PRMT1 and CARM1

et al. 2011

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“…All inhibitors were synthesized from three fragments (A, B, and C) (Figure ). Fragment A was synthesized from the commercially available aspartic acid derivative 6 following the published method by Vederas et al The 5′-deoxy-5′-amino-2′,3′-isopropylideneadenosine ( fragment C) was prepared from protected adenosine 9 as described by Townsend et al Synthesis of fragment B was unique to each inhibitor. Inhibitor 1 used 4-bromoisoquinoline 7 while inhibitors 2 and 3 employed 7,8-dichloroisoquinole 8 as starting materials for the synthesis of the corresponding fragment B.…”

Section: Resultsmentioning

confidence: 99%

Transition-State Analogues of Phenylethanolamine N-Methyltransferase

2020

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Phenylethanolamine N-methyltransferase (PNMT) is a critical enzyme in catecholamine synthesis. It transfers the methyl group of S-adenosylmethionine (SAM) to catalyze the synthesis of epinephrine from norepinephrine. Epinephrine has been associated with diverse human processes, including the regulation of blood pressure and respiration, as well as neurodegeneration found in Alzheimer’s disease. Human PNMT (hPNMT) proceeds through an SN2 transition state (TS) in which the transfer of the methyl group is rate limiting. TS analogue enzyme inhibitors are specific for their target and bind orders of magnitude more tightly than their substrates. Molecules resembling the TS of hPNMT were designed, synthesized, and kinetically characterized. This new inhibitory scaffold was designed to mimic the geometry and electronic properties of the hPNMT TS. Synthetic efforts resulted in a tight-binding inhibitor with a K i value of 12.0 nM. This is among the first of the TS analogue inhibitors of methyltransferase enzymes to show an affinity in the nanomolar range. Isothermal titration calorimetry (ITC) measurements indicated negative cooperative binding of inhibitor to the dimeric protein, driven by favorable entropic contributions. Structural analysis revealed that inhibitor 3 binds to hPNMT by filling the catalytic binding pockets for the cofactor (SAM) and the substrate (norepinephrine) binding sites.

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“…119 The screening of potential affinity ligands and the developments of affinity purification of an S-adenosylmethioninedependent tranferase involved in nocardicin A biosynthesis has been reported. 120…”

Section: -Lactamsmentioning

confidence: 99%

The biosynthesis of plant alkaloids and nitrogenous microbial metabolitesThis review and those that preceded it are dedicated to my three teachers who were each a marvellous scientific inspiration: F. G. Holliman, A. R. Battersby and G. Stork. They were the giants onto whose shoulders I was privileged to climb.

Herbert

2003

Nat. Prod. Rep.

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Inhibitors of an AdoMet-dependent 3-amino-3-carboxypropyl transferase and their use as ligands for protein affinity chromatography

Cited by 10 publications

References 37 publications

Small molecule inhibitors that discriminate between protein arginine N-methyltransferases PRMT1 and CARM1

Small molecule inhibitors that discriminate between protein arginine N-methyltransferases PRMT1 and CARM1

Transition-State Analogues of Phenylethanolamine N-Methyltransferase

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