Activation of an adrenergic pro-drug through sequential stereoselective action of tandem target enzymes.
The synthetic amino acid, 3,4-dihydroxyphenylserine (DOPS) has been of great interest for many years as an adrenergic pro-drug, since the L-threo diastereomer of DOPS can be a precursor of R-(-)-norepinephrine, the natural form of this neurotransmitter. We now report bioactivation of DOPS to the potent pharmacological agent, noradrenalone (arterenone), via sequential stereoselective action by two target enzymes--dopamine beta-monooxygenase (DBM) and L-aromatic amino acid decarboxylase (AADC)--acting in tandem. Enzymatic activation is stereospecific, with only the L-erythro DOPS diastereomer producing noradrenalone; this is consistent with the known stereospecificities of AADC and DBM. These results provide a heretofore unrecognized rationale for the bioactivity of L-erythro DOPS and provide a basis for the design of new adrenergic pro-drugs.
Debnath
J
J
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta 30332.
Husain
P A
PA
May
S W
SW
D000311:Adrenal Glands / Q000201:enzymology; D000818:Animals; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000378:metabolism*; D001711:Biotransformation; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D004299:Dopamine beta-Hydroxylase / Q000378:metabolism*; D015103:Droxidopa / Q000378:metabolism*; D007668:Kidney / Q000201:enzymology; D007700:Kinetics; D011355:Prodrugs / Q000378:metabolism*; D013237:Stereoisomerism; D013379:Substrate Specificity; D013552:Swine
D011355:Prodrugs; D004299:Dopamine beta-Hydroxylase; D001142:Aromatic-L-Amino-Acid Decarboxylases; D015103:Droxidopa