Formation of a new quinone methide intermediate during the oxidative transformation of 3,4-dihydroxyphenylacetic acids: implication for eumelanin biosynthesis.
Oxidation of dopa and dopamine requires a net removal six electrons to produce indolequinones, the monomeric precursors of eumelanin pigment. On the other hand, their 6-fluoroderivatives suffer only four-electron oxidation to yield the same products (M. E. Rice, B. Mogaddam, C. R. Creveling, and K. L. Kirk, Anal. Chem. 59, 1534-1536, 1987). Taking advantage of this novel fluorochemistry, we reexamined the oxidative mechanism of 3,4-dihydroxyphenylacetic acid and 6-fluoro-3,4-dihydroxyphenylacetic acid to throw more light on the nature of reactive intermediates formed during the reaction. Enzymatic or chemical oxidation of 3,4-dihydroxyphenylacetic acid generated the transient o-quinone which exhibited rapid intramolecular cyclization and side chain modification to produce 2, 5,6-trihydrobenzofuran and 3,4-dihydroxymandelic acid, respectively. However, when 6-fluoro-3,4-dihydroxyphenylacetic acid was oxidized either by tyrosinase or by sodium periodate, the resultant quinone uniquely exhibited only cyclization coupled with loss of fluoride ion. This clean reaction allowed us to establish the structures of the transient reactive intermediates. Two interconvertable isomeric forms of the product were isolated and characterized from the reaction mixture. If the oxidation was carried out in water, a yellow quinolactone accumulated in the reaction mixture. This compound was instantaneously converted to a purple quinone methide upon addition of a trace amount of sodium phosphate. Passage through a C(18) HPLC column caused the reverse transformation. The structures of these products were established by semiempirical molecular orbital calculations and NMR spectrometry. Comparison of the oxidation mechanisms of melanin precursors, dopa and dopamine, with that of 3,4-dihydroxyphenylacetic acids reveals that a similar quinone methide intermediate is likely to be formed during eumelanin biosynthesis.
Sugumaran
M
M
Department of Biology, University of Massachusetts-Boston, Boston, Massachusetts 02125, USA. manickam.surumaran@umb.edu
Duggaraju
P
P
Jayachandran
E
E
Kirk
K L
KL
D015102:3,4-Dihydroxyphenylacetic Acid / Q000737:chemistry* / Q000378:metabolism*; D000363:Agaricales / Q000201:enzymology; D004295:Dihydroxyphenylalanine / Q000737:chemistry; D004298:Dopamine / Q000737:chemistry; D045563:Indolequinones; D007211:Indoles / Q000737:chemistry*; D008543:Melanins / Q000096:biosynthesis* / Q000737:chemistry; D008956:Models, Chemical; D015394:Molecular Structure; D014442:Monophenol Monooxygenase / Q000378:metabolism; D010084:Oxidation-Reduction; D011809:Quinones / Q000737:chemistry*; D013053:Spectrophotometry
D045563:Indolequinones; D007211:Indoles; D008543:Melanins; D011809:Quinones; D015102:3,4-Dihydroxyphenylacetic Acid; C041877:eumelanin; C068040:quinone methide; D004295:Dihydroxyphenylalanine; D014442:Monophenol Monooxygenase; D004298:Dopamine