Open Accessδ‐Aminolevulinate Dehydratase Inhibition by 2, 3‐Dimercaptopropanol is Mediated by Chelation of Zinc from a Site Involved in Maintaining Cysteinyl Residues in a Reduced State *
Author(s) -
Emanuelli Tatiana,
Rocha João Batista T.,
Pereira Maria Ester,
Nascimento Paulo C.,
Souza Diogo O. G.,
Beber Flávio A.
Publication year - 1998
Publication title -
pharmacology & toxicology
Language(s) - English
Resource type - Journals
eISSN - 1600-0773
pISSN - 0901-9928
DOI - 10.1111/j.1600-0773.1998.tb01451.x
Subject(s) - chemistry , chelation , zinc , dehydratase , dimercaprol , enzyme , reducing agent , penicillamine , porphobilinogen synthase , biochemistry , metal , stereochemistry , inorganic chemistry , organic chemistry
The mechanisms underlying mouse δ‐aminolevulinate dehydratase (ALA‐D) inhibition by a chelating agent used in the treatment of heavy metal poisoning, 2, 3‐dimercaptopropanol (British Anti‐Lewisite), were investigated. ALA‐D inhibition by 2, 3‐dimercaptopropanol was totally reversed by 25–100 μM Zn 2+ , indicating that inhibition was due to chelation of zinc by 2, 3‐dimercaptopropanol. Our data suggested that zinc bound to a labile site (displaced by 25–40 μM EDTA or 500 μM 2, 3‐dimercaptopropanol) is involved in maintaining the sulfhydryl groups of ALA‐D in a reduced state (essential for enzyme activity), since inhibition by these compounds was reversed by 10 mM dithiotreitol (a reducing agent). On the other hand, 10 mM dithiotreitol did not reverse ALA‐D inhibition by a higher concentration of EDTA (100 μM). Accordingly, 2, 3‐dimercaptopropanol appears to inhibit ALA‐D through a mechanism similar to that of low EDTA concentrations. Neither oxidized 2, 3‐dimercaptopropanol nor reactive oxygen species appeared to contribute for ALA‐D inhibition by reduced 2, 3‐dimercaptopropanol. Taken together, these results suggest that 2, 3‐dimercaptopropanol inhibits ALA‐D by chelating Zn 2+ from a labile site that is involved in maintaining enzyme sulfhydryl groups in a reduced state. This site is compatible with the ZnB or Znβ previously described in mammalian and bacterial ALA‐D.