Ornithine Aminotransferase versus GABA Aminotransferase: Implications for the Design of New Anticancer Drugs

Abstract

Ornithine aminotransferase (OAT) and γ-aminobutyric acid aminotransferase (GABA-AT) are classified under the same evolutionary subgroup and share a large portion of structural, functional, and mechanistic features. Therefore, it is not surprising that many molecules that bind to GABA-AT also bind well to OAT. Unlike GABA-AT, OAT had not been viewed as a potential therapeutic target until recently; consequently, the number of therapeutically viable molecules that target OAT is very limited. In this review the two enzymes are compared with respect to their active site structures, catalytic and inactivation mechanisms, and selective inhibitors. Insight is offered that could aid in the design and development of new selective inhibitors of OAT for the treatment of cancer.

Synthesis and Deployment of an Elusive Fluorovinyl Cation Equivalent: Access to Quaternary α-(1′-Fluoro)vinyl Amino Acids as Potential PLP Enzyme Inactivators

“…In this context, it is noteworthy that in recent years, there has been growing interest in the use of fluorovinyl functionality to inhibit other enzymes, for example, by installing mono- and ( bis -fluoro)vinyl moieties at the γ-position of various GABA analogues 32 to generate compounds with clinical promise for the inhibition of GABA transaminase (epilepsy and drug addiction) 33 and ornithine aminotransferase (hepatocellular carcinoma). 34 …”

A subfamily of PLP-dependent enzymes specialized in handling terminal amines

“…A second Arg residue (Arg141) interacts instead with the γ-carboxylic group of both GABA and α-KG and serves for productive binding and correct positioning of the substrates. This residue is conserved also in other α-KG-specific AT-II transaminases [4,16,60,69]. same substrate; see Table 1), AT-II has been shown to encompass enzymes with bona fide racemase and lyase functions (Table 1 and Fig.…”

“…The presence of this salt bridge helps restrict the binding and reaction of undesired α-amino acids (e.g., glutamate) or α-keto acids, that are required only for the second part of the reaction [16,21,69].…”

“…First, some enzymes in this subgroup are being explored as potential drug targets [16]. Second, it has been shown that, in spite of the name, AT-II also includes enzymes that are not aminotransferases (Table 1).…”

“…Similarly also the β-AT enzymes have been studied only for their biotechnological applications [23]. 16 PKS-ATd was identified as an AT domain belonging to a multi-domain polyketide synthase. It catalyzes the transfer of an amine to the β-position of the growing acyl chain, using glutamine as the best amino donor [106].…”