Metabolic strategies for the degradation of the neuromodulator agmatine in mammals

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

The crystal structure of ATP-bound phosphofructokinase from Trypanosoma brucei reveals conformational transitions different from those of other phosphofructokinases.

The crystal structure of the ATP-bound form of the tetrameric phosphofructokinase (PFK) from Trypanosoma brucei enables detailed comparisons to be made with the structures of the apoenzyme form of the same enzyme, as well as with those of bacterial ATP-dependent and PP(i)-dependent PFKs. The active site of T. brucei PFK (which is strictly ATP-dependent but belongs to the PP(i)-dependent family by sequence similarities) is a chimera of the two types of PFK. In particular, the active site of T. brucei PFK possesses amino acid residues and structural features characteristic of both types of PFK. Conformational changes upon ATP binding are observed that include the opening of the active site to accommodate the two substrates, MgATP and fructose 6-phosphate, and a dramatic ordering of the C-terminal helices, which act like reaching arms to hold the tetramer together. These conformational transitions are fundamentally different from those of other ATP-dependent PFKs. The substantial differences in structure and mechanism of T. brucei PFK compared with bacterial and mammalian PFKs give optimism for the discovery of species-specific drugs for the treatment of diseases caused by protist parasites of the trypanosomatid family

The first crystal structure of phosphofructokinase from a eukaryote: Trypanosoma brucei.

The crystal structure of the ATP-dependent phosphofructokinase (PFK) from Trypanosoma brucei provides the first detailed description of a eukaryotic PFK, and enables comparisons to be made with the crystal structures of bacterial ATP-dependent and PPi-dependent PFKs. The structure reveals that two insertions (the 17-20 and 329-348 loops) that are characteristic of trypanosomatid PFKs, but absent from bacterial and mammalian ATP-dependent PFKs, are located within and adjacent to the active site, and are in positions to play important roles in the enzyme's mechanism. The 90 residue N-terminal extension forms a novel domain that includes an "embracing arm" across the subunit boundary to the symmetry-related subunit in the tetrameric enzyme. Comparisons with the PPi-dependent PFK from Borrelia burgdorferi show that several features thought to be characteristic of PPi-dependent PFKs are present in the trypanosome ATP-dependent PFK. These two enzymes are generally more similar to each other than to the bacterial or mammalian ATP-dependent PFKs. However, there are critical differences at the active site of PPi-dependent PFKs that are sufficient to prevent the binding of ATP. This crystal structure of a eukaryotic PFK has enabled us to propose a detailed model of human muscle PFK that shows active site and other differences that offer opportunities for structure-based drug discovery for the treatment of sleeping sickness and other diseases caused by the trypanosomatid family of protozoan parasites