Behavior of fluorinated analogs of L-(3,4-dihydroxyphenyl)alanine and L-threo-(3,4-dihydroxyphenyl)serine as substrates for Dopa decarboxylase.
We have determined the kinetic parameters for Dopa decarboxylase (DDC) of three ring-fluorinated analogs of 3,4-dihydroxyphenylalanine (Dopa). The rank order of catalytic efficiency of decarboxylation (k(cat)/K(m)) is Dopa>6-F-Dopa>2-F-Dopa>5-F-Dopa. This rank is consistent with previous in vivo and in vitro studies which indicate that, of the fluorinated analogs, 6-F-Dopa has pharmacokinetics that are most suited for positron emission tomographic (PET) evaluation of dopamine function. The effectiveness of PET as a diagnostic tool, the convenient half-life of (18)F (110 min) and the favorable pharmacokinetics of 6-[(18)F]FDOPA have combined to make this an extremely valuable reagent to study dopaminergic activity. The reactions of the related fluorinated DOPS analogs show that, while 6-F-threo-3,4-(dihydroxyphenyl)serine (DOPS) is decarboxylated at approximately the same rate as the non-fluorinated substrate, 2-F-threo-DOPS is not converted into the corresponding amine. In both cases a Pictet-Spengler condensation with the pyridoxal 5(')-phosphate (PLP) cofactor occurs to produce tetrahydroisoquinolines. Condensation of fluorinated catecholamines and catechol amino acids with endogenous aldehydes will be investigated as an approach to study possible mechanisms of L-Dopa-linked neurotoxicity.
Borri Voltattorni
Carla
C
Dipartimento di Scienze Neurologiche e della Visione, Sezione di Chimica Biologica, Facoltà di Medicina e Chirurgia, Università degli Studi di Verona, Verona, Italy. carla.borrivoltattorni@univr.it
Bertoldi
Mariarita
M
Bianconi
Silvia
S
Deng
Wei-ping
WP
Wong
Kelli
K
Kim
InHo
I
Herbert
Brian
B
Kirk
Kenneth L
KL
D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D004296:Dopa Decarboxylase / Q000378:metabolism*; D015259:Dopamine Agents / Q000737:chemistry / Q000378:metabolism*; D015103:Droxidopa / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D005462:Fluorine Radioisotopes; D007700:Kinetics
D015259:Dopamine Agents; D005462:Fluorine Radioisotopes; D004295:Dihydroxyphenylalanine; D004296:Dopa Decarboxylase; D015103:Droxidopa