Insight on the interaction of an agmatinase-like protein with Mn2+ activator ions

Quiñones, Matías; Cofre, Jaime; Benı́tez, José J.; García, David; Romero, Nicol; González, Arlette; Carvajal, Nelson; García, María de los Ángeles Olivares; López, Vasthi; Schenk, Gerhard; Uribe, Elena

doi:10.1016/j.jinorgbio.2015.01.008

Cited by 9 publications

(9 citation statements)

References 29 publications

(43 reference statements)

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“…In this respect, ALP behaves similar to all Mn 2+ -dependent members of the ureohydrolase family, such as the E. coli AGM [30,31] and arginases (ARG) [32][33][34]. In their fully active state, these enzymes contain a binuclear Mn 2+ center, which, according to our results, is also present in ALP [29,35,36]. Due to the lack of structural information and the low degree of sequence identity between ALP and all known ureohydrolases, the active site in ALP is completely unknown.…”

Section: Manganese Binding Site In Alpsupporting

confidence: 76%

“…Regarding the metal ion requirements in ALP agmatinase activity, we have determined that ALP requires Mn 2+ ions for its activity, and the presence of EDTA produces a total inactivation, which is reverted by the addition of metal ions [21,29]. In this respect, ALP behaves similar to all Mn 2+ -dependent members of the ureohydrolase family, such as the E. coli AGM [30,31] and arginases (ARG) [32][33][34].…”

Section: Manganese Binding Site In Alpmentioning

confidence: 99%

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

Reyes

Martínez‐Oyanedel

Navarrete

et al. 2020

IJMS

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Agmatine is a neurotransmitter with anticonvulsant, anti-neurotoxic and antidepressant-like effects, in addition it has hypoglycemic actions. Agmatine is converted to putrescine and urea by agmatinase (AGM) and by an agmatinase-like protein (ALP), a new type of enzyme which is present in human and rodent brain tissues. Recombinant rat brain ALP is the only mammalian protein that exhibits significant agmatinase activity in vitro and generates putrescine under in vivo conditions. ALP, despite differing in amino acid sequence from all members of the ureohydrolase family, is strictly dependent on Mn2+ for catalytic activity. However, the Mn2+ ligands have not yet been identified due to the lack of structural information coupled with the low sequence identity that ALPs display with known ureohydrolases. In this work, we generated a structural model of the Mn2+ binding site of the ALP and we propose new putative Mn2+ ligands. Then, we cloned and expressed a sequence of 210 amino acids, here called the “central-ALP”, which include the putative ligands of Mn2+. The results suggest that the central-ALP is catalytically active, as agmatinase, with an unaltered Km for agmatine and a decreased kcat. Similar to wild-type ALP, central-ALP is activated by Mn2+ with a similar affinity. Besides, a simple mutant D217A, a double mutant E288A/K290A, and a triple mutant N213A/Q215A/D217A of these putative Mn2+ ligands result on the loss of ALP agmatinase activity. Our results indicate that the central-ALP contains the active site for agmatine hydrolysis, as well as that the residues identified are relevant for the ALP catalysis.

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Section: Manganese Binding Site In Alpsupporting

confidence: 76%

Section: Manganese Binding Site In Alpmentioning

confidence: 99%

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

Reyes

Martínez‐Oyanedel

Navarrete

et al. 2020

IJMS

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“…1, A). Agmatinase-like protein (ALP), an isoform of LIM And Calponin Homology Domains 1 (LIMCH1), also has been identified in rodent brain [6]. Notably, peripheral urea cycle dysregulation has been reported in HD [7, 8] and recent studies revealed excess urea [9, 10], deficient ornithine and other urea cycle metabolic perturbations [10] in the post mortem brain tissue of late-stage HD patients.…”

Section: Introductionmentioning

confidence: 99%

Reduced bioavailable manganese causes striatal urea cycle pathology in Huntington's disease mouse model

Bichell

Węgrzynowicz

Tipps

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Huntington’s disease (HD) is caused by a mutation in the huntingtin gene (HTT), resulting in profound striatal neurodegeneration through an unknown mechanism. Perturbations in the urea cycle have been reported in HD models and in HD patient blood and brain. In neurons, arginase is a central urea cycle enzyme, and the metal manganese (Mn) is an essential cofactor. Deficient biological responses to Mn, and reduced Mn accumulation have been observed in HD striatal mouse and cell models. Here we report in vivo and ex vivo evidence of a urea cycle metabolic phenotype in a prodromal HD mouse model. Further, either in vivo or in vitro Mn supplementation reverses the urea-cycle pathology by restoring arginase activity. We show that Arginase 2 (ARG2) is the arginase enzyme present in these mouse brain models, with ARG2 protein levels directly increased by Mn exposure. ARG2 protein is not reduced in the prodromal stage, though enzyme activity is reduced, indicating that altered Mn bioavailability as a cofactor leads to the deficient enzymatic activity. These data support a hypothesis that mutant HTT leads to a selective deficiency of neuronal Mn at an early disease stage, contributing to HD striatal urea-cycle pathophysiology through an effect on arginase activity.

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“…However, the enzyme also requires Mn 2+ for catalytic activity, as evidenced by its complete inactivation when incubated with the metal ion chelator EDTA. The enzymatic activity can, however, easily be recovered by the addition of Mn 2+ to the metal-ion-free apoenzyme [82,86]. In this respect ALP behaves like all well-characterized Mn 2+dependent members of the ureohydrolase family, which include human and rat arginases [87,88] and bacterial AGMs [65,66].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…The lack of sequence homology between these enzymes and ALP limits, in part, our current knowledge of the structure of the active site of the latter. Metal-ion measurements indicate that ALP is likely to contain a bimetallic manganese center in its catalytically optimal form [82,86]. Mutagenesis studies identified up to two Histidine residues that play important roles in Mn 2+ binding in ALP, but the precise structure of the bimetallic metal center awaits further structural studies [86].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Metabolic strategies for the degradation of the neuromodulator agmatine in mammals

et al. 2018

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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.

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Insight on the interaction of an agmatinase-like protein with Mn2+ activator ions

Cited by 9 publications

References 29 publications

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

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

Reduced bioavailable manganese causes striatal urea cycle pathology in Huntington's disease mouse model

Metabolic strategies for the degradation of the neuromodulator agmatine in mammals

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