A Model for the Solution Structure of Human Fe(II)-Bound Acireductone Dioxygenase and Interactions with the Regulatory Domain of Matrix Metalloproteinase I (MMP-I)

Abstract

The metalloenzyme acireductone dioxygenase (ARD) shows metal-dependent physical and enzymatic activities depending upon the metal bound in the active site. The Fe­(II)-bound enzyme catalyzes the penultimate step of the methionine salvage pathway, converting 1,2-dihydroxy-5-(methylthio)­pent-1-en-3-one (acireductone) into formate and the ketoacid precursor of methionine, 2-keto-4-thiomethyl-2-oxobutanoate, using O2 as the oxidant. If Ni­(II) is bound, an off-pathway shunt occurs, producing 3-methylthiopropionate, formate, and carbon monoxide from the same acireductone substrate. The solution structure of the Fe­(II)-bound human enzyme, HsARD, is described and compared with the structures of Ni-bound forms of the closely related mouse enzyme, MmARD. Potential rationales for the different reactivities of the two isoforms are discussed. The human enzyme has been found to regulate the activity of matrix metalloproteinase I (MMP-I), which is involved in tumor metastasis, by binding the cytoplasmic transmembrane tail peptide of MMP-I. Nuclear magnetic resonance titration of HsARD with the MMP-I tail peptide permits identification of the peptide binding site on HsARD, a cleft anterior to the metal binding site adjacent to a dynamic proline-rich loop.

The Role H-Bonding and Supramolecular Structures in Homogeneous and Enzymatic Catalysis

“…The modification of Mn(salen) by forming a supramolecular complex with zinc porphyrinate (due to the H-bond) increases the stability of the catalyst and promotes an increase in the substrate selectivity of the reaction [38] (Figure 2): The methionine salvage pathway (MSP) plays an important role in the regulation of a number of metabolites in prokaryotes and eukaryotes. The MSP is a universal pathway for the conversion of sulfur-containing metabolites into methionine [39]. The two Ni(Fe)ARD enzymes are members of the cupin structural superfamily, which includes Fe-Acetylacetone dioxygenase (Dke1) and cysteine dioxygenase.…”

“…The reaction pathway catalyzed by NiARD does not produce methionine, but the reaction does produce CO, which is a neurotransmitter. CO has been identified as an antiapoptotic molecule in mammals (mouse and human ARD isozymes) (Scheme 2 [39]). A study of the influence of metal ions Fe or Ni, as well as Co and Mn, on the catalytic activity of the mammalian enzyme showed that Fe-ARD, which catalyzes the first pathway, exhibits 10 times higher activity compared to Ni-, Co-, and Mn-containing enzymes that catalyze side reaction pathways.…”

“…In addition to its enzymatic function, studies have shown a role for the ARD enzyme in carcinogenesis and tumor metastasis. Thus, it was recently discovered that the human enzyme regulates the activity of matrix metalloproteinase I (MMP-I), which is involved in tumor metastasis, by binding to the cytoplasmic transmembrane tail peptide MMP-I [39].…”

“…for the conversion of sulfur-containing metabolites into methionine [39]. The two Ni(Fe)ARD enzymes are members of the cupin structural superfamily, which includes Fe-Acetylacetone dioxygenase (Dke1) and cysteine dioxygenase.…”

Role of PhOH and Tyrosine in Selective Oxidation of Hydrocarbons

“…CO has been identified as an anti-apoptotic molecule in mammals. Recently, it was found that a human enzyme regulated the activity of matrix metalloproteinase I (MMP-I), which is involved in tumor metastasis, by binding to the cytoplasmic transmembrane tail peptide MMP-I [19].…”