Dihydroxyphenylalanine, levels

Mechanism of Action A tyrosine hydroxylase inhibitor that blocks conversion of tyrosine to dihydroxyphenylalanine, the rate limiting step in the biosynthetic pathway of catecholamines. Therapeutic Effect Reduces levels of endogenous catecholamines. 

L-Dopa. Dopamine itself cannot penetrate the blood-brain barrier however, its natural precursor, L-dihydroxyphenylalanine (levo-dopa), is effective in replenishing striatal dopamine levels, because it is transported across the blood-brain barrier via an amino acid carrier and is subsequently decarboxy-lated by dopa decarboxylase, present in striatal tissue. Decarboxylation also takes place in peripheral organs where dopamine is not needed and is likely to cause undesirable effects (vomiting hypotension p.116). Extracerebral production of dopamine can be prevented by inhibitors of dopa decarboxylase (carbidopa, benserazide) that do not penetrate the blood-brain barrier, leaving intracerebral decarboxylation unaffected. 

Manganese toxicity has been observed in miners exposed to high levels of Mn02 dust. The neurological symptoms mimic Parkinson s disease. Major changes were observed in the biogenic amines, dihydroxyphenylalanine (DOPA), and phenylalanine. Restoration of appropriate levels of these bioamines alleviated the symptoms. Chelation therapy has not been demonstrated as an effective strategy. ... 

It was named Dopamine because it was a monoamine, and its synthetic precursor was 3,4-dihydroxyphenylalanine (L-DOPA). He was awarded Nobel Prize in 2000 along with Eric Kandel and Paul Greengard in Medicine for showing that dopamine is not just a precursor of noradrenaline and adrenaline, but also neurotransmitter as well. DO is a type of neurotransmitter naturally produced in by the human body. It is also a neurohormone released by the hypothalamus. It is a chemical messenger that is similar to adrenaline and affects the brain processes that control movement, emotional response, and the capacity to feel pleasure and pain. It is vital for performing balanced and controlled movements [172,173], In the extra-cellular fluid of the central nervous system, the basal DO concentration is very low (0.01-1 pM). Abnormal levels of DO have been linked with Parkinson s disease, Tourette s syndrome, Schizophrenia, attention deficit hyperactive disorder and generation of pituitary tumours [174-176],... 

The synthesis of dopamine originates from the precursor the amino acid L-tyrosine, which must be transported across the blood-brain barrier into the dopaminergic neuron. The rate limiting step in the synthesis is the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-DOPA) by the enzyme tyrosine hydroxylase (TH). L-DOPA is subsequently converted to dopamine by aromatic L-amino acid decarboxylase. The latter enzyme turns over so rapidly that L-DOPA levels in the brain are negligible under normal conditions.1... 

Treatment of biopterin and biopterin reductase deficiency consists not only of regulating the blood levels of phenylalanine but of supplying the missing form of coenzyme and the precursors of neurotransmitters, namely, dihydroxyphenylalanine and 5-hydroxytryptophan, along with a compound that inhibits peripheral aromatic decarboxylation. This compound is necessary because the amine products do not cross the blood-brain barrier. 

Fates of tyrosine. Tyrosine can be degraded by oxidative processes to ace-toacetate and fumarate which enter the energy generating pathways of the citric acid cycle to produce ATP as indicated in Figure 38-2. Tyrosine can be further metabolized to produce various neurotransmitters such as dopamine, epinephrine, and norepinephrine. Hydroxylation of tyrosine by tyrosine hydroxylase produces dihydroxyphenylalanine (DORA). This enzyme, like phenylalanine hydroxylase, requires molecular oxygen and telrahydrobiopterin. As is the case for phenylalanine hydroxylase, the tyrosine hydroxylase reaction is sensitive to perturbations in dihydropteridine reductase or the biopterin synthesis pathway, anyone of which could lead to interruption of tyrosine hydroxylation, an increase in tyrosine levels, and an increase in transamination of tyrosine to form its cognate a-keto acid, para-hydroxyphenylpyruvate, which also would appear in urine as a contributor to phenylketonuria. 

Tyrosine is actively transported into nerve endings and is converted to dihydroxyphenylalanine DOPA) via tyrosine hydroxylase 1). This step is rate limiting in the synthesis of NE. DOPA is converted to dopamine (DA) via L-aromatic amino acid decarboxylase (DOPA decarboxylase). DA in turn is metabolized to NE via DA beta hydroxylase and is taken up and stored in granules (6). Inactivation ofNE via monoamine oxidase (MAO) (2) may regulate prejunctional levels of transmitter in the mobile pool (3) but not the NE stored in granules. 

Table VII. Levels of Dopamine and Dihydroxyphenylalanine (DOPA) in Females, Males, and Eggs of the Bulb Mite...

Low levels of the neurotransmitter dopamine in the brain have been linked to Parkinson s disease. Oral administration of L-dihydroxyphenylalanine (l-DOPA), the biosynthetic precursor to dopamine, has been successful in treating the symptoms of Parkinson s disease. The key to this success is that l-DOPA is capable of crossing the blood-brain barrier while dopamine is not (Scheme 4). Once in the brain, l-DOPA is decarboxy-lated by the enzyme aromatic amino acid decarboxylase (AAD) to give dopamine. Prior to entering the brain l-DOPA is susceptible to metabolism by several different enzymes. The initial entry into metabolism is also... 

Kojic acid and arbutin are tyrosinase inhibitors. Kojic acid inhibits tyrosinase activity by chelation and as an antioxidant, while arbutin is a competitive inhibitor of tyrosinase. To impart hydrophobicity to these compounds to prevent degradation, phosphatidyl-kojic acid and phosphatidyl-arbutin were synthesized from dipalmitic-PC (DPPC) [43]. Their inhibition of l-DOPA (3,4-dihydroxyphenylalanine) to dop-achrome (precursor of melanin), catalyzed by tyrosinase in vitro, was of a similar level to the parent compounds. These phosphatidyl derivatives show promise for application in the cosmetics industry. 

Note that L-dihydroxyphenylalanine (L-dopa) is an intermediate in the conversion of tyrosine. Lower-than-normal levels of L-dopa are involved in Parkinson s disease. Tyrosine or phenylalanine supplements might increase the levels of dopamine, though L-dopa, the immediate precursor, is usually prescribed because L-dopa passes into the brain quickly through the blood-brain barrier. 

Noradrenaline (NAdr = norepinephrine, NE) is formed by the stereospecific oxidation of the fl-carbon of dopamine, which itself is formed by the decarboxylation of l-DOPA (L-3,4-dihydroxyphenylalanine). Epinephrine (Adr) is formed by the Af-methylation of norepinephrine. Thus, a compound that blocks the enzyme dopa decarboxylase (responsible for the decarboxylation of dopa) causes a decline in the level of catecholamines, such as dopamine and norepinephrine, and hypotensive activity is expected. The absolute stereostructures of norepinephrine and epinephrine were determined by the transformation of each of these alkaloids into R-mandelic acid [1]. 

Phenylalanine, tyrosine, and 34-dihydroxyphenylalanine (DOPA) decarboxylases have been found in several plants. Each causes the formation of the corresponding amine. Phen-ylethylamine (8) and tyramine (9) are widespread among plants and may occur at high levels. These amines are common in the Cactaceae, Fabaceae, Rosaceae, and Rutaceae (Wagner, 1988). 

Similar chemical reactions are involved in the reaction of other catechols such as the catecholamines, dopamine, and L-dihydroxyphenylalanine (L-DOPA) with cysteine or GSH [149-152] and can lead to the generation of mitochondrial toxins with relevance to Parkinson s disease [153-155], As well as possible cytotoxic effects of lowering cellular thiol levels or binding to cysteine residues at die active site of specific enzymes, flavonoids could act beneficially by acting to limit the formation of the potentially cytotoxic catecholamine-thiol adducts, in a manner similar to that observed for dihydro-lipoic acid [151], Because of the structural similarity of the flavonoid B-ring and their ability to donate electrons efficiently to form quinones, it is conceivable that specific flavonoids may be of use to prevent such neurotoxic compounds as 5-S-cysteinyl dopamine from forming in vivo. 

Based on the measurement of PLP in deproteinized plasma by addition of L-3,4-dihydroxyphenylalanine and apo-tyrosine decarboxylase the dopamine formed is measured by HPLC and the concentration found is directly proportional to the PLP level in the sample. 

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