Metabolite carrier

Lehninger, A. L. Metabolite carriers in mitochondrial membranes. In The Ca++ transport system in the dynamic structure of cell membranes, pp. 119. Wallach, D. F. H., Fisher, H. (eds.). New York, Heidelberg, Berlin Springer 1971... 

The carrier protein facilitating Pj and phosphate ester transport is of particular interest in leaves in connection with carbon processing - i.e., the synthesis, transport and degradation of carbohydrate, all of which occur in the cytosol [51]. This metabolite carrier, called the phosphate translocator, is a polypeptide with a molecular mass of 29 kDa and is a major component of the inner envelope membrane [52,53]. The phosphate translocator mediates the counter-transport of 3-PGA, DHAP and Pj. The rate of Pj transport alone is three orders of magnitude lower than with simultaneous DHAP or 3-PGA counter-transport [54]. Consequently operation of the phosphate translocator keeps the total amount of esterified phosphate and Pj constant inside the chloroplast. Significantly, the carrier is specific for the divalent anion of phosphate. 

The availability of oxaloacetate, which acts as the metabolite carrier in the Krebs cycle, may also be limited. The production of oxaloacetate is achieved by acetyl-CoA-induced stimulation of pyruvate carboxylase (Sec. 11.8 Fig. 11-17). 

Metabolites of vitamin D, eg, cholecalciferol (CC), are essential in maintaining the appropriate blood level of Ca ". The active metabolite, 1,25-dihydroxycholecalciferol (1,25-DHCC), is synthesized in two steps. In the fiver, CC is hydroxylated to 25-hydroxycholecalciferol (25-HCC) which, in combination with a globulin carrier, is transported to the kidney where it is converted to 1,25-DHCC. This step, which requites 1-hydroxylase formation, induced by PTH, may be the controlling step in regulating Ca " concentration. The sites of action of 1,25-DHCC are the bones and the intestine. Formation of 1,25-DHCC is limited by an inactivation process, ie, conversion of 25-HCC to 24,25-DHCC, catalyzed by 24-hydroxylase. 

The citric acid cycle, a nine-step process, also diverts chemical energy to the production of ATP and the reduction of NAD and FAD. In each step of the citric acid cycle (also known as the Krebs cycle) a glucose metabolite is oxidized while one of the carrier molecules, NAD or FAD, is reduced. Enzymes, nature s chemical catalysts, do a remarkable job of coupling the oxidation and reduction reactions so that energy is transferred with great efficiency. 

According to a hypothesis launched by Larionov et al in the 1960s, some new nitrogen mustard derivatives were developed. They contain metabolites and heterocyclic structures as carriers of the cytotoxic chloroethylamine groups. By this way the synthesis of aliylating metabolites started melphalan (sarcolysine) as L- or DL-phenylalanine derivative prospidine with a tricyclic piperazine moiety and chlorambucil as butyric acid derivative. It was proven that each alkylating metabolite has its own spectrum of selective antitumor activity. 

Glucose- 6-phosphate dehydrogenase Low or absent enzyme activity in about 10% of African populations. Hemolysis following intake of a number of drugs which have electrophilic reactive metabolites, but also, carriers of this enzyme deficiency have a partial protection from malaria. 

Plasma protein fractions include human plasma protein fraction 5% and normal serum albumin 5% (Albuminar-5, Buminate 5%) and 25% (Albuminar-25, Buminate 25%). Plasma protein fraction 5% is an IV solution containing 5% human plasma proteins. Serum albumin is obtained from donated whole blood and is a protein found in plasma The albumin fraction of human blood acts to maintain plasma colloid osmotic pressure and as a carrier of intermediate metabolites in the transport and exchange of tissue products. It is critical in regulating the volume of circulating blood. When blood is lost from shock, such as in hemorrhage, there is a reduced plasma volume. When blood volume is reduced, albumin quickly restores the volume in most situations. 

It is clearly impossible to give a comprehensive overview of this rapidly expanding field. I have chosen a few experts in their field to discuss one (class of) transport protein(s) in detail. In the first five chapters pumps involved in primary active transport are discussed. These proteins use direct chemical energy, mostly ATP, to drive transport. The next three chapters describe carriers which either transport metabolites passively or by secondary active transport. In the last three chapters channels are described which allow selective passive transport of particular ions. The progress in the latter field would be unthinkable without the development of the patch clamp technique. The combination of this technique with molecular biological approaches has yielded very detailed information of the structure-function relationship of these channels. 

Typically, neurotoxic effects of drugs on monoamine neurons have been assessed from reductions in brain levels of monoamines and their metabolites, decreases in the maximal activity of synthetic enzymes activity, and decreases in the active uptake carrier. In the present study, the traditional markers described above have been used, including the measurement of the content of monoamines and their metabolites in brain at several different timepoints following drug administration. Since reports in the literature have documented that MDMA and MDA can inhibit the activity of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin synthesis (Stone et al. 1986 Stone et al. 1987). it is unclear whether MDMA-induced reductions in the content of serotonin and its metabolite 5-hydroxyin-doleacetic acid (5-HlAA) may be due to suppressed neurotransmission in otherwise structurally intact serotonin neurons or may represent the eonsequenee of the destruction of serotonin neurons and terminals. 

The neurotoxic effects of all these compounds are antagonized by inhibitors of monoamine uptake (table 1), implicating the membrane uptake carrier on serotonin and dopamine neurons in the mechanism of neurotoxicity. In this regard, these amphetamines are like a drug somewhat related in structure, namely l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP), a Parkinsonism-causing neurotoxic dmg that has been studied intensely since 1983 (Langston and Irwin 1986). In the case of MPTP, the mechanism by which inhibitors of the dopamine uptake carrier block the neurotoxicity toward dopamine neurons (mainly nigrostriatal dopamine neurons) seems clear. A metabolite of MPTP, l-methyl-4-phenylpyridinium (MPP-I-), has been shown to be a substrate for the dopamine uptake carrier (Javitch et al. 1985). Thus accumulation of MPP-I-, formed metabolically from... 

Drug Membrane Uptake Carrier Involved in Neurotoxicity Drug Metabolite Involved in Neurotoxicity... 

A second approach might be to measure dopamine and serotonin along with their metabolites and other specific neuronal constituents such as tyrosine hydroxylase and tryptophan hydroxylase or uptake carrier sites in brain tissue obtained at autopsy. Accumulating data in this way might be a slow and tedious process, and drug dosing history might be uncertain and variable nonetheless, the approach deserves consideration. 

The ultimate fate of drugs and their metabolites is a major concern. If they are not cleared in a reasonable time, they could promote undesirable side effects. Polymer drug carriers are usually nonbiodegradable, and if their size is greater than 40,000 daltons, they could accumulate in the host with the potential of future unwanted effects. 

Nomura and Ogata provided the first evidence that tunicates can produce PGs [17]. Using a rat stomach fundus bioassay, Halocynthia roretzi tissues were shown to possess low levels of PGs. The testes showed higher levels (9 ngg-1 wet tissue) than ovary and muscle tissue. The sea-squirt Styela clava did not show PGs by this method. No structures were determined in this work. Reexamination of the ability of H, roretzi to produce PGs was carried out by Ogata and coworkers [19]. Incubation of selected tissues with 14C-labeled eicosa-8,11,14-trienoic acid and subsequent isolation of PGE and PGF fractions after addition of carrier showed the branchial tissue to have the highest conversion levels. Quantitation was done by LSC. Using a TLC radioscanner, the authors determined that fractions with metabolites similar to PGE and PGF... 

Blood is the transport medium of the body. Plasma, which accounts for approximately 60% of the total volume, carries a wide range of small and medium-sized metabolites some are simply dissolved in solution (93% of the plasma is water), others are carried by specific carrier proteins. The chemical composition of the plasma is complex and reflects the chemical composition inside cells, which is why blood tests are so commonly used in diagnosis to see the biochemical events occurring in tissues. The formed cellular elements of the blood perform several functions defence against blood loss from bleeding (platelets, also called thrombocytes), defence against infection and immune surveillance (white cells, leucocytes), and gas transport and pH buffering (red cells, erythrocytes). 

---