Metabolic precursors

Aromatic biguanides such as proguanil (181) have been found useful as antimalarial agents. Investigation of the metabolism of this class of drugs revealed that the active compound was in fact the triazine produced by oxidative cyclization onto the terminal alkyl group. The very rapid excretion of the active entity means that it cannot be used as such in therapy. Consequently, treatment usually consists in administration of either the metabolic precursor or, alternately, the triazine as some very insoluble salt to provide slow but continual release of drug. 

The immediate metabolic precursor to dopamine, l-DOPA (L-dihydroxphenylalanine) is converted to the active neurotransmitter dopamine by the action of the enzyme aromatic amine acid decarboxylase (AADC). l-DOPA (INN name Levodopa) is the main diug used to treat Parkinson s disease. 

While metabolic engineers traditionally sought the rate-limiting enzyme to unlock flow through a pathway, now they understand that there may be many points of control and feedback with the metabolic network, and seek to empirically determine the dynamics of the interactions between rate controllers and other factors. For example, the sizes of metabolic precursor pools and the catabolism or sequestration of products affect accumulation as well as flux through the pathway. 

Studies using either molecular oxygen-18 or oxygen-18 water indicated that the 4R,5R-dihydrodiol is derived by water attack at the C-4 position of the metabolically formed 4,5-epoxide intermediate (15.21), These results established that 4S,5R-epoxide is formed as the metabolic precursor of the 4R,5R-dihydrodiol. Hydration studies of the optically pure BaP 4,5-epoxide enantiomers indicated that the 4S,5R-epoxide is hydrated exclusively at the S-center (C-4 position) whereas 85% of the 4R,5S-epoxide is hydrated at the S-center (C-5 position) (22 and Figure 4). 

Tumorigenicity of tetrahydroepoxides. As yet, only Ch H -epoxide has been directly demonstrated to be tumorigenic (18). However, indirect evidence has been found in the high tumorigenicity of 3,4-dihydro BA, 9,10-dihydro BeP and 3,4-dihydrobenz[c]acridine (19-21), each of which is a likely metabolic precursor of a bay-region H -epoxide. In the case of 9,10-dihydro BeP, cis- and trans-9,10-dihydroxy -9,10,11,12-tetrahydro BeP were identified as products of metabolism of 9,10-dihydro BeP (22), and are the expected products of hydration of the epoxide. Diols are also formed from 7,8-dihydro BaP upon metabolism with prostaglandin endoperoxide synthase (23) or with rat liver homogenates (24). 

Myelin components exhibit great heterogeneity of metabolic turnover. One of the novel characteristics of myelin demonstrated in early biochemical studies was that its overall rate of metabolic turnover is substantially slower than that of other neural membranes [1]. A standard type of experiment was to evaluate lipid or protein turnover by injecting rat brains with a radioactive metabolic precursor and then follow loss of radioactivity from individual components as a function of time. Structural lipid components of myelin, notably cholesterol, cerebro-side and sulfatide, as well as proteins of compact myelin, are relatively stable, with half-lives of the order of many months. One complication in interpreting these studies is that the metabolic turnover of individual myelin components is multiphasic - consisting of an initial rapid loss of radioactivity followed by a much longer slower loss. 

Tyrosine is structurally related to and derived from phenylalanine. It is the metabolic precursor to dopamine, an important neurotransmitter. Tyrosine is also the precursor to the hormones epinephrine and norepinephrine and to melanin, the pigment of skin. 

Histidine is characterized by a heterocyclic side chain known as imidazole. The imidazole group will bear a positive charge under physiological conditions. Histidine is the metabolic precursor to histamine, a potent inflammatory molecule. Antihistamines work by antagonizing the action of histamine. 

Aspartic acid has a side chain carboxyl group that will lose a proton and become an anionic carboxylate group under physiological conditions. Aspartic acid is the metabolic precursor to gamma (y)-aminobutyric acid (GABA), an important inhibitory neurotransmitter in the human central nervous system. 

Amino acids have a larger role to play in life than serving as the building blocks of proteins, itself an absolutely critical role. Specifically, several of the amino acids are key metabolic precursors to families of products. That is, these amino acids are the starting point for one or a series of chemical transformations, all catalyzed by... 

Tyrosine is also the metabolic precursor to the neurotransmitter dopamine and the catecholamine hormones norepinephrine (noradrenaline) and epinephrine (adrenaline), as well as to the alkaloids in opium, including morphine. 

Now here is the central nnderstanding—the role of several vitamins is to serve as coenzymes or as metabolic precursors for coenzymes that is, the vitamin itself may serve as coenzyme or it may be converted in the human body to a coenzyme. The other key point 1 suppose is obvious but 1 am going to state it anyway we need vitamins in our diet because we cannot make them ourselves. In that sense, they are like essential amino acids or essential fatty acids stuff that we need but cannot make ourselves and so must obtain from dietary sources. So let s get started in understanding these critical molecules and how they serve the needs of human beings. 

The role of several vitamins in human physiology is to act as coenzymes or as metabolic precursors for coenzymes. 

Vitamin B2, or riboflavin, is the metabolic precursor to two flavin coenzymes essential for the integrity of a spectrum of redox reactions. 

Niacin, which refers to nicotinic acid and nicotinamide, is the metabolic precursor to three nicotinamide coenzymes. These are essential for the activity of a large number of enzymes catalyzing redox reactions. Pellagra is a niacin deficiency disease. 

The vitamin Be family of molecules are metabolic precursors to pyridoxal phosphate, an essential coenzyme for multiple enzymes involved in amino acid metabolism. 

Pantothenic acid is a metabolic precursor to coenzyme A, which is involved in a very large number of reactions that occur in all phases of metabolism. 

Cholesterol is absolutely required in human physiology (a) as a constituent of biological membranes and (b) as the metabolic precursor to all other steroids. 

Finally, carotenoids are the metabolic precursors for three more of the flavor volatiles of the tomato. Although the role of carotenoids, light-harvesting pigments in plants, in human nutrition is the subject of debate, these compounds are antioxidants and P-carotene is the principal source of the visual pigments of the eye. 

Dopa (t-dopa) a metabolic precursor of dopamine useful in the treatment of parkinsonism. 

A test system that involves extraeting dichlorobenzidine or its metabolite (monoacetyldichlorobenzidine) from urine and reaeting it with Chloramine-T has been developed to screen for dichlorobenzidine exposure in workers (Hatfield et al. 1982). An amperometric method has been developed for the detection of 3,3 -dichlorobenzidine in the urine as a quantitative assay for the biological monitoring of people oeeupationally exposed to this substance or a metabolic precursor such as certain pigments. This method is based on the possibility of two electron oxidation at carbon electrodes by aromatic diamines (Trippel-Sehulte et al. 1986). 

Fluoroacetate undergoes a "lethal synthesis"(18) to 2-fluorocitrate which may reversibly inhibit aconitase and which irreversibly binds to a membrane-associated citrate transport protein(19,20). Insecticidal and other biocidal uses of fluoroacetate (or its metabolic precursors) received considerable attention twenty-five years ago( ) but most uses have been abandoned due to high nonspecific vertebrate toxicity of these compounds. Vfe have reported the use of o)-fluoro fatty acids and their derivatives as delayed-action toxicants for targeted... 

Moore RM, Jr, Wolf BS, Stein HP, et al Metabolic precursors of a known human carcinogen. Science 195 344, 1977... 

Recently we have been working on Parkinson s disease. This and other similar diseases are due to a depletion of dopamine in the corpus striatum. Direct addition of dopamine is not effective in the treatment presumably because it does not cross the blood-brain barrier. However, levodopa, the metabolic precursor of dopamine, does cross the blood brain barrier and is believed to then be converted to dopamine in the basal ganglia. 

Dhar, A., Desai, K., Kasachmov, M., Yu, P., and Wu, L. (2008). Methylglyoxal production in vascular smooth muscle cells from different metabolic precursors. Metabolism 57, 1211-1220. 

Other photosensitisers in clinical or pre-clinical trials include zinc phthalocya-nine, aluminium sulphonated phthalocyanines, benzoporphyrins, benzochlorins and purpurin-lS-iV-alkylamides, all of which absorb strongly in the 675-700 nm region. An alternative approach to the photosensitisation in PDT involves the use of 5-aminolaevulinic acid (ALA). This compound itself is not a sensitiser but in human cells it is the key metabolic precursor in the biosynthesis of protoporphyrin IX, which can act as a photosensitiser. Normally the biosynthetic process would continue beyond protoporphyrin IX to the iron containing haem. However, by adding extra ALA and iron chelators, the ferrochelatase action is inhibited and the normal feedback mechanism by-passed resulting in a build up of protoporphyrin IX in the cell. The mechanism is illustrated in Figure 4.24. ... 

Levodopa, the metabolic precursor of dopamine, is the most effective agent in the treatment of Parkinson s disease but not for drug-induced Parkinsonism. Oral levodopa is absorbed by an active transport system for aromatic amino acids. Levodopa has a short elimination half-life of 1-3 hours. Transport over the blood-brain barrier is also mediated by an active process. In the brain levodopa is converted to dopamine by decarboxylation and both its therapeutic and adverse effects are mediated by dopamine. Either re-uptake of dopamine takes place or it is metabolized, mainly by monoamine oxidases. The isoenzyme monoamine oxidase B (MAO-B) is responsible for the majority of oxidative metabolism of dopamine in the striatum. As considerable peripheral conversion of levodopa to dopamine takes place large doses of the drug are needed if given alone. Such doses are associated with a high rate of side effects, especially nausea and vomiting but also cardiovascular adverse reactions. Peripheral dopa decarboxylase inhibitors like carbidopa or benserazide do not cross the blood-brain barrier and therefore only interfere with levodopa decarboxylation in the periphery. The combined treatment with levodopa with a peripheral decarboxylase inhibitor considerably decreases oral levodopa doses. However it should be realized that neuropsychiatric complications are not prevented by decarboxylase inhibitors as even with lower doses relatively more levodopa becomes available in the brain. 

It is an immediate metabolic precursor of noradrenaline. It activates Dj receptors in several vascular beds, which causes vasodilatation. It acts on dopaminergic and other adrenergic receptors (a P ). 

Dopamine does not cross the blood-brain barrier and if given into the peripheral circulation has no therapeutic effect in parkinsonism. However, (-)-3-(3,4-dihydroxyphenyl)-L-alanine (levodopa), the immediate metabolic precursor of dopamine, does enter the brain (via an L-amino acid transporter, LAT), where it is decarboxylated to dopamine (see Figure 6-5). Several noncatecholamine dopamine receptor agonists have also been developed and may lead to clinical benefit, as discussed in the text that follows. 

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