Metabolic strategies for the degradation of the neuromodulator agmatine in mammals

Abstract

Agmatine (1-amino-4-guanidinobutane), a precursor for polyamine biosynthesis, has been identified as an important neuromodulator with anticonvulsant, antineurotoxic and antidepressant actions in the brain. In this context it has emerged as an important mediator of addiction/satiety pathways associated with alcohol misuse. Consequently, the regulation of the activity of key enzymes in agmatine metabolism is an attractive strategy to combat alcoholism and related addiction disorders. Agmatine results from the decarboxylation of L-arginine in a reaction catalyzed by arginine decarboxylase (ADC), and can be converted to either guanidine butyraldehyde by diamine oxidase (DAO) or putrescine and urea by the enzyme agmatinase (AGM) or the more recently identified AGM-like protein (ALP). In rat brain, agmatine, AGM and ALP are predominantly localised in areas associated with roles in appetitive and craving (drug-reinstatement) behaviors. Thus, inhibitors of AGM or ALP are promising agents for the treatment of addictions. In this review, the properties of DAO, AGM and ALP are discussed with a view to their role in the agmatine metabolism in mammals.

Rational Design of Potent Inhibitors of a Metallohydrolase Using a Fragment‐Based Approach

“…For example, the Ni II -dependent urease is a target to treat digestive tract ailments, [96][97][98] while the Fe II -and/or Mn IIdependent cyclic diesterase Rv0805 is a novel target for inhibitors that could treat tuberculosis, [99] and the Mn II -dependent agmatinases gain momentum as possible targets for novel medications to treat neurological and addiction-related disorders. [100][101][102] However, to date, no inhibitors of this group of enzymes have made it to application in clinical practice. This may, in part, be due to their active sites lacking a defined pocket and/or the bimetallic catalytic centers have similar geometries that make the design of selective inhibitors challenging.…”

Insights into the Mn2+ Binding Site in the Agmatinase-Like Protein (ALP): A Critical Enzyme for the Regulation of Agmatine Levels in Mammals

“…Considering that ALP has emerged as a central enzyme in regulating crucial neurological processes, a detailed understanding of its interaction with Mn 2+ and how its activity is controlled will be essential in defining this enzyme as a promising drug target to treat human afflictions [35,45].…”

Safety and neurochemical profiles of acute and sub-chronic oral treatment with agmatine sulfate

“…It is of interest to note that oral agmatine treatment resulted in decreased putrescine levels in the hippocampus regardless of dosage and delivery route, but increased putrescine levels in plasma in a dose-dependent manner, with no changes in L-arginine and other metabolites. Agmatine is known to be an alternative precursor for the putrescine biosynthesis through agmatinase and/or agmatinase-like protein (in rats), but can also induce antizyme to inhibit the activity of ornithine decarboxylase that converts L-ornithine to putrescine 7,8,37 . The differential pattern of agmatine-induced changes in putrescine in the brain and plasma demonstrates differential actions of exogenous agmatine on the central (brain) and peripheral organs, which merits future research to understand the underlying mechanisms and functional significance.…”