Cloning of human agmatinase. An alternate path for polyamine synthesis induced in liver by hepatitis B virus

Abstract

Agmatinase, which hydrolyzes agmatine to putrescine and urea, not only represents a potentially important mechanism for regulating the biological effects of agmatine in mammalian cells but also represents an alternative to ornithine decarboxylase for polyamine biosynthesis. We have isolated a full-length cDNA encoding human agmatinase whose function was confirmed by complementation in yeast. The single-copy human agmatinase gene located on chromosome 1 encodes a 352-residue protein with a putative mitochondrial targeting sequence at the NH(3)-terminus. Human agmatinase has about 30% identity to bacterial agmatinases and <20% identity to mammalian arginases. Residues required for binding of Mn(2+) at the active site in bacterial agmatinase and other members of the arginase superfamily are fully conserved in human agmatinase. Agmatinase mRNA is most abundant in human liver and kidney but also is expressed in several other tissues, including skeletal muscle and brain. Its expression in human liver is induced during hepatitis B virus infection, suggesting that agmatinase may play a role in the pathophysiology of this disease.

Arginase Plays a Pivotal Role in Polyamine Precursor Metabolism in Leishmania

“…In the AGM pathway, arginine is decarboxylated by arginine decarboxylase to produce agmatine, which is then hydrolyzed to putrescine with the resultant liberation of a urea molecule. Recently, AGM has also been identified in mammalian cells (67,68), although the existence of an arginine decarboxylase is still unresolved. The AGM pathway does not appear to contribute to the putrescine pool in Leishmania promastigotes, because ⌬odc (18) and ⌬arg promastigotes are putrescine auxotrophs.…”

Insights into the reaction mechanism of Escherichia coli agmatinase by site‐directed mutagenesis and molecular modelling

“…Agmatine, which results from decarboxylation of arginine by arginine decarboxylase [2], is a metabolic intermediate in the biosynthesis of putrescine and higher polyamines [1] and may have important regulatory roles in mammals [3][4][5].…”

“…Schizosaccharomyces pombe and Bacillus subtilis, have been cloned and the deduced amino acid sequences indicate their homology to all sequenced arginases [4][5][6][7]; all these enzymes catalyse an hydrolytic reaction with production of urea. The question arises therefore as to whether a similar or identical mechanism is involved in catalysis by these enzymes, which apparently evolved from a single primordial protein [6,7].…”

L-Arginine Metabolism in the Lung: Reciprocal Regulation of the NOS and Arginase Pathways

“…The conversion of L-arginine into agmatine is the most recently demonstrated pathway of L-arginine metabolism in mammals, and its significance in health and disease remains largely unknown [80]. In addition to a direct agonist effect on imidazoline receptors, agmatine also represents an alternative pathway for the synthesis of polyamines, as it is converted into putrescine and urea by agmatinase, a member of the arginase superfamily [81]. Interestingly, agmatine is also capable of inducing antizyme, and thus paradoxically reduces cellular polyamine content and proliferation through inhibition of ornithine decarboxylase [82].…”