Membrane transport systems, inhibitors

Inhibitors of HMG-CoA reductase activity (for example compac-tin240), or compounds that lower the levels of the enzyme (including a number of oxygenated cholesterol derivatives,241- 24 la such as 25-liy-droxycholesterol), not only decrease the formation of polyprenyl diphosphate, but also affect the formation of cholesterol and the polyprenyl side-chains of coenzyme Q. Consequently, prolonged treatment with such compounds may cause side effects, for example, changes in membrane fluidity (see also, Section III,5), decreased activity of membrane enzymes,1214,2,3 and inactivation of membrane transport systems,246 and, therefore, indirectly prevent glvcosvlation of proteins. 

Intensive use of the herbicide paraquat has resulted in the evolution of resistance in various weed species. Intensive research on the resistance mechanisms was mainly carried out with resistant biotypes from Hordeum spp. and Conyza spp., and altered distribution of the herbicide in the resistant weeds was suggested as the cause - or at least the partial cause - of resistance. In resistant Conyza canadensis it was supposed that a paraquat inducible protein may function by carrying paraquat to a metabolically inactive compartment, either the cell wall or the vacuole. This sequestration process would prevent the herbicide from getting in sufficient amounts into the chloroplasts as the cellular site of paraquat action. Inhibitors of membrane transport systems, e.g., N,N-dicyclohexylcarbodii-mide (DCCD), caused a delay in the recovery of photosynthetic functions of the paraquat-resistant biotype, when given after the herbicide. These transport inhibitor experiments supported the involvement of a membrane transporter in paraquat resistance [75]. 

The transport system that conveys malate and a-ketoglu-tarate across the inner mitochondrial membrane (see Fig. 19-27) is inhibited by n-butylmalonate. Suppose n-butyl-malonate is added to an aerobic suspension of kidney cells using glucose exclusively as fuel. Predict the effect of this inhibitor on (a) glycolysis, (b) oxygen consumption, (c) lactate formation, and (d) ATP synthesis. 

Figure 1. The channels which can be available for proton release in different cells. These may be activated by ligands attached to receptors or signals generated by the electron transport system. The electron transport across the membrane can also be accompanied by proton movement, depending on the orientation of electron transport, but th is movement would be I imited because of the slow rate of electron transport compared to the rapid rate which can be elicited through channels. Any possible relation of oxidase control to the H+-ATPase or the H -K+-ATPase has not been tested by inhibitors such as bafilomycin or omeprazole, respectively (Swallow et al., 1990).

Within the past few years, there has been considerable progress in understanding the role played by the mitochondria in the cellular homeostasis of iron. Thus, erythroid cells devoid of mitochondria do not accumulate iron (7, 8), and inhibitors of the mitochondrial respiratory chain completely inhibit iron uptake (8) and heme biosynthesis (9) by reticulocytes. Furthermore, the enzyme ferrochelatase (protoheme ferro-lyase, EC 4.99.1.1) which catalyzes the insertion of Fe(II) into porphyrins, appears to be mainly a mitochondrial enzyme (10,11,12,13, 14) confined to the inner membrane (15, 16, 17). Finally, the importance of mitochondria in the intracellular metabolism of iron is also evident from the fact that in disorders with deranged heme biosynthesis, the mitochondria are heavily loaded with iron (see Mitochondrial Iron Pool, below). It would therefore be expected that mitochondria, of all mammalian cells, should be able to accumulate iron from the cytosol. From the permeability characteristics of the mitochondrial inner membrane (18) a specialized transport system analogous to that of the other multivalent cations (for review, see Ref. 19) may be expected. The relatively slow development of this field of study, however, mainly reflects the difficulties in studying the chemistry of iron. 

Cytochrome cdj needs three things to reduee nitrite to nitric oxide, substrates nitrite and protons plus eleetrons. The first two are simply supplied from the environment but where do the eleetrons eome from Cytochrome cdi derives its electrons from the eleetron transport system in the cytoplasmic membranes of baeteria. Thus, for example, eleetrons ean originate from NADH and pass via NADH dehydrogenase, ubiquinone/ubiquinol and the cytochrome bc eomplex to nitrite reduetase (Berks et al., 1995 Zumft, 1997). It is known that the eytoehrome bc eomplex is used beeause electron transfer from physiologieal donors, e.g. NADH, to nitrite reduetase is blocked by specific inhibitors, e.g. myxothiazol, of this complex. An important issue arises when we eonsider how electrons are transferred from the cytochrome fccj complex to eytoehrome cd, which, recall, is a water-soluble protein located in the periplasm. The structure of the cytochrome be I complex (determined for the mitoehondrial protein but we can assume that the bacterial counterparts are similarly organised) shows that the... 

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