Abstract: This Proteopedia article presents a series of five conceptually linked Proteopedia pages about mammalian serine hydrolases. Over 110 different human serine hydrolases have been identified, assigned diverse biological roles, and targeted for the treatment of common diseases. Interestingly, with their diverse functions, the majority of serine hydrolases are built from the same protein scaffold (α/β hydrolase fold) and use the same catalytic machinery (catalytic triad of serine, histidine, and an acidic residue). In five-linked Proteopedia pages, we have presented the complex interplay between the structure, enzymatic mechanism, biological function, and therapeutic potential of five mammalian serine hydrolases. Specifically, Proteopedia pages were constructed about protein palmitoylation thioesterase (PPT1), dipeptidyl peptidase IV, fatty acid amide hydrolase (FAAH), monoglyceride lipase, and hormone sensitive lipase. Structure–function stories contained on the Proteopedia pages include a description of the conserved α/β hydrolase domain (Fig. 1a) and a map of the multiple mutations to PPT1 linked to juvenile neurological disorders. The classic enzymatic mechanisms of serine hydrolases are also illustrated, along with variations like the Ser-Ser-Lys catalytic triad in FAAH (Fig. 1b). Therapeutic inhibition of serine hydrolases is also shown through covalent and noncovalent cocrystallization studies (Fig. 1c). Serine hydrolases are often used as model proteins for introducing enzyme kinetics, mechanisms, and inhibition in biochemistry courses. Thus, these Proteopedia pages will serve as a resource where students can explore the interplay between the structure and enzymatic properties of serine hydrolases and can learn about the interesting biology connected to their enzymology. Serine hydrolases: conserved structure, classic enzymology, and interesting biology. (a) Classic α/β hydrolase fold of MGL (PDB code: 3JW8). The central eight-stranded β-sheet (seven parallel and one antiparallel; purple) is surrounded by α-helices (blue). (b) Unusual Ser–Ser–Lys catalytic triad of FAAH (PDB code: 1MT5). The nucleophilic serine is covalently bound to methyl arachidonyl fluorophosphonate (purple and orange) and is hydrogen bonded (yellow) to the accessory serine and lysine residues. (c) Inhibition of serine hydrolases. Dimeric structure of DPP IV (PDB code: 1X70) with a noncovalently bound β-amino acid inhibitor (yellow). Inhibitors of DPP IV are used in the treatment of Type II diabetes. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Publication Year: 2014
Publication Date: 2014-11-18
Language: en
Type: article
Indexed In: ['crossref', 'pubmed']
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Cited By Count: 1
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