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Molecular Aspects of the Activity and Inhibition of the FAD-Containing Monoamine Oxidases
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
FAD, a redox cofactor important for catalysis in many enzymes, is derived from the vitamin riboflavin. As in most FAD-containing enzymes, the adenine part of the molecule binds to a Rossman fold in the protein. The isoalloxazine ring part of FAD is held in position by a covalently bond to a cysteine residue in MAO (Fig. 10.3). In all crystal structures of MAO B, the isoalloxazine ring is bent by about 30° (Binda et al., 2003) with about 0.3° difference between the oxidized and reduced forms. However, molecular dynamics has now enabled a more realistic picture of the shape of the flavin in the flexible protein active site. Two different studies have shown that it is almost planar in the oxidized form (FAD) (Vianello et al., 2012; Zapata-Torres et al., 2015), but when it is reduced either by a hydride ion from the substrate transferred to N5 in the first step of the catalytic mechanism or after the propargylamine adduct has formed at N5, the FADH2 is bent by almost 30 degrees (Borstnar et al., 2011) in agreement with the crystal structure.
Mupirocin
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Isoleucyl–tRNA synthesis occurs in two steps. First, the intermediate isoleucyl-adenylate (isoleucyl–adenosine monophosphate [AMP]) is generated from isoleucine and adenosine triphosphate (ATP). The second step involves the transfer of this intermediate to the 3′-terminus of the corresponding tRNA. This isoleucyl–tRNA complex subsequently delivers the isoleucines to ribosomes during protein synthesis. Mupirocin acts as an analog of isoleucyl-AMP by binding to the catalytic cleft of the tRNA synthetase, called the Rossman fold domain. Competitive inhibition of this enzyme arrests protein synthesis (Hughes and Mellows, 1978).
Phosphoglycerate dehydrogenase (PHGDH) inhibitors: a comprehensive review 2015–2020
Published in Expert Opinion on Therapeutic Patents, 2021
Quentin Spillier, Raphaël Frédérick
In 2016, AstraZeneca reported the first series of orthosteric PHGDH inhibitors based on an indole scaffold (Figure 2) [25]. The discovery strategy of this compound is based on a high throughput screening (HTS) of a library of fragments by crystal soaking. The screening led to the identification of numerous fragments, including the hit 1, which is characterized by a benzothiophene scaffold binding in the NAD-binding site and which demonstrates an interesting ligand efficiency (LE = 0.39). This fragment was then extended to improve its interaction with the Rossman fold and the 3-PG pocket leading to the development of 2, a more potent inhibitor with still excellent ligand efficiency (LE = 0.37). Successive rounds of optimizations finally led to a series of indole derivatives presenting submicromolar inhibition. The lead compound in this series, the indole 3, exhibits a Kd of 0.18 µM and a good LE of 0.29. The formation of a key hydrogen bond between the carboxylate of 3 and the Arg236 residue of PHGDH contributed to the high inhibitory potency of this compound.
Sirtuins: potential therapeutic targets for regulating acute inflammatory response?
Published in Expert Opinion on Therapeutic Targets, 2020
Vidula Vachharajani, Charles E. McCall
The sirtuins depend on NAD+ for their enzyme activation [2]. Notably, sirtuin activation requires adequate concentrations of NAD+ in the compartment in which they reside, or to which they transfer [8]. Sirtuins are a highly conserved family of proteins, with a core catalytic domain of 275 amino acids. This core is flanked by N- and C-terminal extensions which determine sirtuin activity and subcellular localization [9]. The catalytic core of sirtuin contains two sub-domains. The larger sub-domain consists of Rossman fold for NAD+ binding and a smaller domain, inserted in the Rossman fold, is formed by a zinc-binding motif and α-helical regions. The acetyl-lysine containing polypeptide and NAD+ substrates bind to the interface of these two domains [9–11]. These form a ‘cofactor binding loop’ where the catalytic events occur. The catalytic events comprise of covalent 1ʹ O-alkylamide intermediate between two substrates with nicotinamide release. This intermediate is further hydrolyzed to form deacetylated substrate polypeptide and 2ʹ-O-acetyl-ADP-ribose [9]. Evidence suggests significant conformational changes to the sirtuin molecule upon deacetylation [9].
Synthesis, biological activity and molecular modelling studies of shikimic acid derivatives as inhibitors of the shikimate dehydrogenase enzyme of Escherichia coli
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Dulce Catalina Díaz-Quiroz, César Salvador Cardona-Félix, José Luis Viveros-Ceballos, Miguel Angel Reyes-González, Franciso Bolívar, Mario Ordoñez, Adelfo Escalante
Shikimate dehydrogenase (SDH, E.C. 1.1.1.25), the fourth enzyme in the SA pathway catalyses the reversible reduction of 3-dehydroshikimate (DHS) to SA using NADPH as co-substrate. SDH is a member of an oxide-reductase family whose crystallographic structure in several organisms have been determined either in the apoenzyme form or binary and ternary complexes12. The shared three-dimensional fold consists of two α/β domains linked by a pair of α-helices, the substrate-binding site is mainly delineated by residues from the N-terminal domain whereas the cofactor binding site is comprising in the C-terminal domain that adopts a Rossmann fold. Functional and structural studies on SDH enzymes opened a platform for the development of SDH inhibitors as few reports exist compared to other enzymes of the SA pathway.