The dual face of endogenous alpha-aminoketones: pro-oxidizing metabolic weapons.
Amino metabolites with potential prooxidant properties, particularly alpha-aminocarbonyls, are the focus of this review. Among them we emphasize 5-aminolevulinic acid (a heme precursor formed from succinyl-CoA and glycine), aminoacetone (a threonine and glycine metabolite), and hexosamines and hexosimines, formed by Schiff condensation of hexoses with basic amino acid residues of proteins. All these metabolites were shown, in vitro, to undergo enolization and subsequent aerobic oxidation, yielding oxyradicals and highly cyto- and genotoxic alpha-oxoaldehydes. Their metabolic roles in health and disease are examined here and compared in humans and experimental animals, including rats, quail, and octopus. In the past two decades, we have concentrated on two endogenous alpha-aminoketones: (i) 5-aminolevulinic acid (ALA), accumulated in acquired (e.g., lead poisoning) and inborn (e.g., intermittent acute porphyria) porphyric disorders, and (ii) aminoacetone (AA), putatively overproduced in diabetes mellitus and cri-du-chat syndrome. ALA and AA have been implicated as contributing sources of oxyradicals and oxidative stress in these diseases. The end product of ALA oxidation, 4,5-dioxovaleric acid (DOVA), is able to alkylate DNA guanine moieties, promote protein cross-linking, and damage GABAergic receptors of rat brain synaptosome preparations. In turn, methylglyoxal (MG), the end product of AA oxidation, is also highly cytotoxic and able to release iron from ferritin and copper from ceruloplasmin, and to aggregate proteins. This review covers chemical and biochemical aspects of these alpha-aminoketones and their putative roles in the oxidative stress associated with porphyrias, tyrosinosis, diabetes, and cri-du-chat. In addition, we comment briefly on a side prooxidant behaviour of hexosamines, that are known to constitute building blocks of several glycoproteins and to be involved in Schiff base-mediated enzymatic reactions.
Bechara
Etelvino J H
EJH
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, 05508-900, São Paulo, SP, Brazil. Electronic address: ebechara@iq.usp.br.
Dutra
Fernando
F
Centro de Ciências Biológicas e da Saúde, Universidade Cruzeiro do Sul, São Paulo, SP, Brazil.
Cardoso
Vanessa E S
VES
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, 05508-900, São Paulo, SP, Brazil.
Sartori
Adriano
A
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, 05508-900, São Paulo, SP, Brazil.
Olympio
Kelly P K
KPK
Faculdade de Saúde Pública, Universidade de São Paulo, São Paulo, SP, Brazil.
Penatti
Carlos A A
CAA
Department of Physiology, Dartmouth Medical School, Hanover, NH, USA.
Adhikari
Avishek
A
Department of Biological Sciences, Columbia University, New York, NY, USA.
Assunção
Nilson A
NA
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, 05508-900, São Paulo, SP, Brazil.
D000096:Acetone / Q000031:analogs & derivatives* / Q000378:metabolism; D000622:Aminolevulinic Acid / Q000378:metabolism*; D000818:Animals; D003410:Cri-du-Chat Syndrome / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism; D006595:Hexosamines / Q000378:metabolism*; D006801:Humans; D050111:Imino Sugars / Q000378:metabolism*; D007855:Lead Poisoning / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology; D017118:Porphyria, Acute Intermittent / Q000378:metabolism; D051381:Rats
D006595:Hexosamines; D050111:Imino Sugars; D016877:Oxidants; D000096:Acetone; D000622:Aminolevulinic Acid; C006495:aminoacetone