Disease relevance of 6-Ohdopa

• We have evaluated the chemotherapeutic potential of 2,4-dihydroxyphenylalanine, a targeted prodrug that can be hydroxylated by tyrosinase (monophenol monooxygenase, EC 1.14.18.1) within melanoma cells to form the cellular toxin 2,4,5-trihydroxyphenylalanine (6-hydroxydopa) [1].
• Evidence for copper and 3,4,6-trihydroxyphenylalanine quinone cofactors in an amine oxidase from the gram-negative bacterium Escherichia coli K-12 [2].
• Here we examined the ability of BDNF to confer protection on cultured dopaminergic neurons against the neurotoxic effects of 6-hydroxyDOPA (TOPA or 2,4,5-trihydroxyphenylalanine), a metabolite of the dopamine pathway suggested to participate in the pathology of Parkinson's disease [3].
• These results suggest that opiates and endorphins may enhance sprouting of noradrenergic neurons following neonatal treatment with 6-OHDOPA, by increasing the toxicity of this neurotoxin [4].
• While a high dose of 6-OHDOPA (15 mug/mul) decreased the body weight, an increase of weight was observed after a low dose (4 mug/0.5 mul) [5].

High impact information on 6-Ohdopa

• In CAOs, the cofactor is 2,4,5-trihydroxyphenylalanine quinone (TPQ), and in LOX it is lysine tyrosyl quinone (LTQ) [6].
• Among these, the copper amine oxidases catalyze the oxidative deamination of primary amines utilizing a type(II) copper center and 2,4,5-trihydroxyphenylalanine quinone (TPQ), a covalent cofactor derived from the post-translational modification of an active site tyrosine [7].
• Investigation of Cu(I)-dependent 2,4,5-trihydroxyphenylalanine quinone biogenesis in Hansenula polymorpha amine oxidase [7].
• Both 3,4-dihydroxyphenylalanine and 2,4,5-trihydroxyphenylalanine were oxidized with periodate and mushroom tyrosinase to determine whether the latter compound is an intermediate in melanin biosynthesis [8].
• To accomplish this transformation, CAOs utilize two cofactors: a mononuclear copper, and a unique redox cofactor, 2,4,5-trihydroxyphenylalanine quinone (TPQ or TOPA quinone) [9].

Chemical compound and disease context of 6-Ohdopa

• PPLO, a copper amine oxidase (CuAO) with a 2,4,5-trihydroxyphenylalanine quinone (TPQ) cofactor, differs from most other members of the CuAO enzyme family in having the ability to oxidize the side chain of lysine residues in a polypeptide [10].

Biological context of 6-Ohdopa

• Application of Michaelis-Menten kinetics indicated a decrease in the Vmax for 3H-NE uptake in the hypothalamus of 6-OHDOPA (60 mug/g i.p., two doses, 48-hour intervals from birth)-treated rats, sacrificed at 6 months of age [11].
• The enzymes are dimers of identical 70-90 kDa subunits, each of which contains a single copper ion and a covalently bound cofactor formed by the post-translational modification of a tyrosine side chain to 2,4,5-trihydroxyphenylalanine quinone (TPQ) [12].
• The high affinity, Na+-independent L-[3H]glutamate binding process in synaptic membranes and in the purified binding protein was shown to be inhibited to an almost equal extent by the metal ligands NaN3, KCN, and o-phenanthroline, and by 2,4,5-trihydroxyphenylalanine (6-OH DOPA) [13].
• The hydroxylation branch of o-dopaquinone-H+ only operates significantly at pH < or = 5.0 and involves the accumulation of 2,4,5-trihydroxyphenylalanine (topa), which has been detected by high-performance liquid chromatography (HPLC) [14].

Anatomical context of 6-Ohdopa

• After 6-OHDA, 6-OHDA plus DMI or the high dose of 6-OHDOPA the DA concentration dropped significantly in the amygdala while low-dose 6-OHDOPA resulted in DA increase [5].
• In 6-month-old rats that were treated on day of birth with 6-OHDOPA (60 mg/kg, i.p.) there was a 32% loss of nerve cell bodies in the locus coeruleus [15].
• By 13 days there was a further increase in the relative number of fluorescent fibers in the cerebellar cortex of the morphine +6-OHDOPA group, as compared to the group treated with 6-OHDOPA alone [16].
• Basal content of 2,5-DHBA, the enzymatically formed spin trap product, was 4-fold higher vs. 2,3-DHBA in the neostriatum of untreated rats, while L-DOPA and 6-OHDOPA each reduced formation of 2,5-DHBA [17].

Associations of 6-Ohdopa with other chemical compounds

• This cofactor, 2,4,5-trihydroxyphenylalanine quinone (TPQ), is formed within the active site of these enzymes by the oxidation of a single tyrosine residue [18].
• On the basis of published crystallographic structures, the asparagine is found to reside proximal to the active site redox cofactor, 2,4,5-trihydroxyphenylalanine quinone (TPQ) [19].
• 6-Hydroxydopamine (6-OHDA) or 6-hydroxydopa (6-OHDOPA) were injected bilaterally into the central part of amygdala [5].
• Neonatal treatment with 6-OHDOPA markedly potentiated TRH-induced locomotor stimulation and behavioral arousal in the 7-day-old rat but not in the 14-day-old and adult rat [20].
• The behavioral effect of thyrotropin releasing hormone (TRH) was investigated in the developing rat pretreated with 6-OHDOPA at birth [20].

Gene context of 6-Ohdopa

• Brain-derived neurotrophic factor selectively rescues mesencephalic dopaminergic neurons from 2,4,5-trihydroxyphenylalanine-induced injury [3].
• Much exogenously administered 6-OHDOPA is biotransformed by aminoacid decarboxylase (AADC) to the highly potent and catecholamine-(CA) selective neurotoxin, 6-hydroxydopamine (6-OHDA) [21].

Analytical, diagnostic and therapeutic context of 6-Ohdopa

• 6-OHDOPA destroys locus coeruleus noradrenergic perikarya and produces associated denervation of brain by norepinephrine-(NE) containing fibers [21].
• By 7 days the relative number of fibers in the 6-OHDOPA groups was similar to that seen in the control group, but by 9 days the relative number of fluorescent fibers in the cerebellar cortex was increased above control [16].

References