OCCURRENCE AND CHEMISTRY OF DIHYDROXYFUMARIC ACID

N. Secara et al./Chem. J. Mold. 2011, 6 (1), 29-44 OCCURRENCE AND CHEMISTRY OF DIHYDROXYFUMARIC ACID N. Secara, Gh. Duca, L. Vlad, F. Macaev* Institute of Chemistry of the Academy of Sciences of Moldova, 3 Academy str., MD-2028, Chisinau, Moldova Tel +373-22-739-754, Fax +373-22-739-954, E-mail: Dedicated to academician Pavel F. Vlad on the occasion of his 75th birthday Abstract: The paper summarizes literature data on occurrence of dihydroxyfumaric acid and its role in biological systems, as well as its chemical properties. Keywords: dihydroxyfumaric acid, fluorescent sensors, molecular clips, coordination polymers 1. Introduction The role of many hydroxy acids, such as malic, lactic, glycolic, citric, tartaric, in living organisms and plant metabolism is generally recognized. The interest in plant metabolites as sources of biologically active compounds appeared a long time ago. One of the leaders, due to its potential, in the series of natural sources is the dihydroxyfumaric acid 1. It is clear that discovery of the relationship between structures and properties can conduct to successful development of new effective antioxidants, drugs etc. In this paper, we tried to systemize literature data based on occurrence of dihydroxyfumaric acid 1 in biological sources and synthetic transformations into target products, which should be convenient (from our point of view) for the chemists. This approach is presented in our review. 2. Structure and occurrence of dihydroxyfumaric acid in biological systems Dihydroxyfumaric acid is 1 a dicarboxylic hydroxy acid, which is formed from tartaric acid via dehydrogenation or oxidation processes. For the first time, it was chemically obtained in 1894 by Fenton, as a product of tartaric acid oxidation by hydrogen peroxide, in the presence of Fe(II) [1,2]. Dihydroxyfumaric acid has trans- and cis- isomers. The trans- isomer is called the dihydroxyfumaric acid, and the cis- isomer is called the dihydroxymaleic acid. Fenton suggested that the dihydroxyfumaric acid mainly exists in its cis- form, therefore in all scientific work before 1950’s, the acid is referred to as dihydroxymaleic. At the beginning of the XXth century it was proved [3] that these forms are chemically identical, and in 1953 Hartree [4] showed that in crystalline form, as well as in solution, only the trans- isomer exists. Also, it should be mentioned that dihydroxyfumaric acid in solution exists in two tautomeric forms in equilibrium (Scheme 1): HO HO2 C CO2 H HO OH HO2 C CO2 H O 1 Scheme 1 In solution, 80 % of the acid usually corresponds to the enolic group, and the other 20% - to the keto-group [5]. Similarly to tartaric acid, dihydroxyfumaric acid (DHF) plays an important role in nature. The first proofs of its biological significance appeared in 1915 when Neuberg [6] observed that DHF was fermented by yeast. In 1938 Banga and Szent-Gyiirgyi [7] and Banga and Philippot [8] extracted an enzyme, which they called dihydroxyfumaric acid oxidase from plants; the oxidation product was later proved to be diketosuccinic acid. In 1940 Theorell also discovered an enzyme in some plants, which oxidized dihydroxyfumaric acid with oxygen uptake, and he proved that enzyme to be peroxidase. It was shown that the active centers of dihydroxyfumaric acid oxidase and peroxidase are the coordination compounds of iron ad copper [9]. As it was previously said, these ferments catalyze the transformation of DHF into diketosuccinic acid 2. HO CO2 H HO 2C OH +1/2 O 2 + DHF oxidase CO2 H O O HO 2C 2 1 Scheme 2 29 Chemistry Journal of Moldova. General, Industrial and Ecological Chemistry. 2011, 6 (1), 29-44 Therefore, it was suggested [9] that in the system oxygen + DHF-oxidase, the role of DHF is similar to that of ascorbic acid 3 in the ascorbate-oxidase system which afforded α-diketone 4 (see Scheme 3). HO H HO O O HO +1/2 O2 + L-ascorbate oxidase O O HO OH HO H O O 3 4 Scheme 3 It may be observed from these schemes that the dihydroxyfumaric acid bears some similarities with the ascorbic acid, and therefore, in biological oxidation, it may play a similar role to that of ascorbate, i.e. intermediate hydrogen carrier from substrates to oxygen. The oxidase function of peroxidase was later shown towards other compounds, such as: glutathione, hydro- and naphtoquinone, fluoroglycine and others. A necessary condition for the oxydase reaction was proved to be the presence of cofactors – manganese ions and various phenolic compounds. Further information on certain enzymatic reactions of dihydroxyfumaric and diketosuccinic acids in plant tissues was obtained by Stafford, Magaldi, and Vennesland [10] in 1954. The role of dihydroxyfumaric acid in animal metabolism was evidenced for the first time in 1934 when it was found that the content of glycogen was increased in muscle on incubation with DHF [11]. Latter, was discovered a sequence of enzyme reactions as a pathway for glyconeogenesis, based on the observation suggesting the formation of a pentose (or a pentose phosphate) on addition of DHF and glyceraldehydes (or fructose-l,6-diphosphate and aldolase as a source of glyceraldehyde-3-phosphate) in rabbit muscle extract. The sequence of reactions leading from DHF to 3-ketopentose 5 is given as follows [12]. CO2 CO2 HO CO2H HO CO2 H HO2C OH 1 HO HO2C CH2 OH OHC O CH 2 OH OHC CH2 OH HO O OH CH 2OH CO2H 5 HO2C CO2 Scheme 4 It is well known that di – and tricarboxylic organic acids play an important role in plant and animal metabolism. Products of carbohydrates transformations, they participate in the biosynthesis of alkaloids, glycosides, amino acids and other biologically active compounds. The dihydroxyfumaric acid is linked to the cycle of di- and tricarboxylic acids, and with the glyoxalic cycle via tartaric acid transformation cycle, as depicted below, in Figure 1. Without going into details, it should be mentioned that the main function of these cycles consists in that they represent the final collective path of oxidation of carbohydrates, lipids and proteins, as during metabolism processes, glucose, fatty acids and amino acids are transformed either into acetyl-CoA, or in intermediate compounds of cycles mentioned above. The dihydroxyfumaric acid is formed from tartaric acid by dehydrogenation, in the presence of nicotinamide adenine dinucliotide (NAD) and tartaric acid dehydrogenase, and bivalent iron. The dihydroxyfumaric acid is involved in metabolism during grapes ripening. Although it is found in small amounts in grapes, it serves as a catalyst for redox reactions. Dihydroxyfumaric acid is easily oxidized by DHF oxidase. Therefore, grapes contain the products of its disintegration: mesoxalic acid, glycolic acid and oxalic acid and glyoxalic acid. Dihydroxyfumaric acid is of importance in winemaking industry and in food industry. It is well known that organic acids contribute to the formation of acidity of wines – one of the major impo (...truncated)