Functional analysis of the Mn2+ requirement in the catalysis of ureohydrolases arginase and agmatinase - a historical perspective

Uribe, Elena; Reyes, María-Belen; Martı́nez, Ignacio; Mella, Kelly; Salas, Mónica; Tarifeño-Saldivia, Estefanía; López, Vasthi; García-Robles, María De Los Ángeles; Martínez‐Oyanedel, José; Figueroa, Maximiliano; Carvajal, Nelson; Schenk, Gerhard

doi:10.1016/j.jinorgbio.2019.110812

Cited by 24 publications

(26 citation statements)

References 47 publications

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“…We hope and believe that the evolution of the theories concerning the mechanism of this key enzyme, described and discussed in this mini review, could inspire the new generations of bioinorganic chemists to resolve the mysteries still shrouded in the chemistry of the active sites of other metalloenzymes. In the same context, it is interesting to highlight the close relationship of the structure and chemistry of urease with a number of related metallohydrolases [74,75] such as arginase and agmatinase [76] as well as purple acid phosphatases [77], which feature a similar di-metallic active site containing manganese and iron in place of nickel.…”

Section: Resultsmentioning

confidence: 99%

The structure-based reaction mechanism of urease, a nickel dependent enzyme: tale of a long debate

2020

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This review is an attempt to retrace the chronicle that starts from the discovery of the role of nickel as the essential metal ion in urease for the enzymatic catalysis of urea, a key step in the biogeochemical cycle of nitrogen on Earth, to the most recent progress in understanding the chemistry of this historical enzyme. Data and facts are presented through the magnifying lenses of the authors, using their best judgment to filter and elaborate on the many facets of the research carried out on this metalloenzyme over the years. The tale is divided in chapters that discuss and describe the results obtained in the subsequent leaps in the knowledge that led from the discovery of a biological role for Ni to the most recent advancements in the comprehension of the relationship between the structure and function of urease. This review is intended not only to focus on the bioinorganic chemistry of this beautiful metal-based catalysis, but also, and maybe primarily, to evoke inspiration and motivation to further explore the realm of bio-based coordination chemistry.

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Section: Resultsmentioning

confidence: 99%

The structure-based reaction mechanism of urease, a nickel dependent enzyme: tale of a long debate

2020

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“…Many arginases have their highest catalytic activity with Mn 2+ as a metal cofactor, but also have some activity with other divalent transition metals [39,40]. The S. meliloti 6His-Sumo-ArgI1 assayed at pH 8 has significant activity with three different transition metal cofactors, in the order Ni 2+ > Mn 2+ > Co 2+ .…”

Section: Discussionmentioning

confidence: 99%

Genetic regulation, biochemical properties and physiological importance of arginase from Sinorhizobium meliloti

et al. 2020

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In bacteria, l-arginine is a precursor of various metabolites and can serve as a source of carbon and/or nitrogen. Arginine catabolism by arginase, which hydrolyzes arginine to l-ornithine and urea, is common in nature but has not been studied in symbiotic nitrogen-fixing rhizobia. The genome of the alfalfa microsymbiont Sinorhizobium meliloti 1021 has two genes annotated as arginases, argI1 (smc03091) and argI2 (sma1711). Biochemical assays with purified ArgI1 and ArgI2 (as 6His-Sumo-tagged proteins) showed that only ArgI1 had detectable arginase activity. A 1021 argI1 null mutant lacked arginase activity and grew at a drastically reduced rate with arginine as sole nitrogen source. Wild-type growth and arginase activity were restored in the argI1 mutant genetically complemented with a genomically integrated argI1 gene. In the wild-type, arginase activity and argI1 transcription were induced several fold by exogenous arginine. ArgI1 purified as a 6His-Sumo-tagged protein had its highest in vitro enzymatic activity at pH 7.5 with Ni2+ as cofactor. The enzyme was also active with Mn2+ and Co2+, both of which gave the enzyme the highest activities at a more alkaline pH. The 6His-Sumo-ArgI1 comprised three identical subunits based on the migration of the urea-dissociated protein in a native polyacrylamide gel. A Lrp-like regulator (smc03092) divergently transcribed from argI1 was required for arginase induction by arginine or ornithine. This regulator was designated ArgIR. Electrophoretic mobility shift assays showed that purified ArgIR bound to the argI1 promoter in a region preceding the predicted argI1 transcriptional start. Our results indicate that ArgI1 is the sole arginase in S. meliloti , that it contributes substantially to arginine catabolism in vivo and that argI1 induction by arginine is dependent on ArgIR.

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“…For example, it has been reported that Asn81 stabilizes the binuclear Mn 2+ center of metallophosphoesterase from a marine bacteria [39], and Asn233 plays a similar role in the binuclear Zn 2+ center of the betalactamase of Bacillus cereus [40]. Furthermore, The enzyme can accommodate two closely spaced Mn 2+ ions in their active sites, using highly conserved amino acid side chains [18]. AGM belongs to the ureohydrolases enzyme family, which requires bivalent ions for its catalytic activity, especially Mn 2+ .…”

Section: Manganese Binding Site In Alpmentioning

confidence: 99%

“…AGM belongs to the ureohydrolases enzyme family, which requires bivalent ions for its catalytic activity, especially Mn 2+ . On the active site, six strictly conserved amino acid residues are responsible for metal coordination; four Asp and two His residues [18][19][20], as shown in Figure 1B. While AGM from Escherichia coli has been extensively studied, a detailed characterization of mammalian AGM is still lacking.…”

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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Functional analysis of the Mn2+ requirement in the catalysis of ureohydrolases arginase and agmatinase - a historical perspective

Cited by 24 publications

References 47 publications

The structure-based reaction mechanism of urease, a nickel dependent enzyme: tale of a long debate

The structure-based reaction mechanism of urease, a nickel dependent enzyme: tale of a long debate

Genetic regulation, biochemical properties and physiological importance of arginase from Sinorhizobium meliloti

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

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