Cell Surface Reductases

As we saw in the previous section, Strategy 1 plants utilize ferric reductases, with NADPH as electron donor, coupled to proton extrusion and a specific Fe(II) transport system localized in the root plasma membrane. Saccharomyces cerevisiae also uses cell surface reductases to reduce ferric iron, and in early studies (Lesuisse et ah, 1987 ... 

A diverse assemblage of phytoplankton and macroalgae, including diatoms, coccolithophorids (Palenik and Morel, 1988), charophytes (Ivankina and Novak, 1988), and cyanobacteria (Peschek et al., 1988) reduce extracellular electron acceptors. For example, the coastal diatom, Thalassiosira weissflogii, reduces Cu(II) and Fe(III) complexes via three independent reductants as shown in Fig. 3 (Jones et al., 1987) (1) Reductants released by the cells and free in solution that are quickly consumed and are not regenerated in the absence of cells, (2) cell surface moieties that are also rapidly exhausted and can be inactivated by pretreatment with oxidants, and (3) a cell surface reductase whose activity is light-independent. 

LDL (apo B-lOO, E) receptors occur on the cell surface in pits that are coated on the cytosolic side of the cell membrane with a protein called clathrin. The glycoprotein receptor spans the membrane, the B-lOO binding region being at the exposed amino terminal end. After binding, LDL is taken up intact by endocytosis. The apoprotein and cholesteryl ester are then hydrolyzed in the lysosomes, and cholesterol is translocated into the cell. The receptors are recycled to the cell surface. This influx of cholesterol inhibits in a coordinated manner HMG-CoA synthase, HMG-CoA reductase, and, therefore, cholesterol synthesis stimulates ACAT activ-... 

In the rhizosphere, microorganisms utilize either organic acids or phytosiderophores to transport iron or produce their own low-molecular-weight metal chelators, called siderophores. There are a wide variety of siderophores in nature and some of them have now been identified and chemically purified (54). Pre.sently, three general mechanisms are recognized for utilization of these compounds by microorganisms. These include a shuttle mechanism in which chelators deliver iron to a reductase on the cell surface, direct uptake of metallated siderophores with destructive hydrolysis of the chelator inside the cell, and direct uptake followed by reductive removal of iron and resecretion of the chelator (for reviews, see Refs. 29 and 54). 

Reported applications of DST include the crosslinking of ubiquinone cytochrome C reductase (Smith et al., 1978), characterization of the cell surface receptor for colony-stimulating factor (Park et al., 1986), investigation of the Ca+2-, Mg+2-activated ATP of E. coli (Bragg and Hou, 1980), and characterization of human properdin polymers (Farries and Atkinson, 1989). 

It is SREBPs which coordinate the expression of HMG CoA reductase and cell surface receptors for LDL. Cholesterol is an essential component of membranes so if delivery of cholesterol to the cell is limited by low concentrations of LDL-cholesterol, the expression of the genes for both the LDL receptor and HMG CoA reductase are up-regulated allowing the cell to extract as much as possible form the circulation and also to synthesize cholesterol, thus there is an inverse relationship between plasma LDL-cholesterol concentration and HMG CoA reductase activity. 

Mechanism of Action Inhibit HMG-CoA reductase, preventing the conversion of HMG-CoA to mevalonate, an early step in cholesterol biosynthesis Depletion of cellular cholesterol stimulates the production of cell surface receptors that recognize LDL, leading to increased catabolism of LDL cholesterol ... 

Some mutant mice have extended lifespans. The Ames dwarf mouse has a mutation in p66shc, a cell-surface protein that contains both Src-homology and collagen-homology domains. It lives almost one-third longer than do wild-type mice.538 Mice deficient in methionine sulfoxide reductase have a reduced lifespan539 but fruit flies with overexpressed activity of the enzyme are more resistant than wild-type flies to oxidative damage.540... 

A close connection exists between the regulation of cholesterol biosynthesis and uptake. When HMG-CoA reductase is inhibited, the cell responds by synthesizing more LDL receptors to ensure the uptake of cholesterol from the serum. When cholesterol is present in a high enough concentration in the cell, LDL receptors are not exported to the cell surface, an example of the phenomenon of down regulation. 

A drug receptor is a specialized target macromolecule, present on the cell surface or intracellularly, that binds a drug and mediates its pharmacologic actions. Drugs may interact with enzymes (for example, inhibition of dihydrofolate reductase by trimethoprim, p. 294),... 

Figure 1 Copper transport pathway. Copper is absorbed in the intestine and becomes bound to amino acids, mainly histidine and albumin. Prior to uptake, Cu(II) is reduced to Cu(I) by a membrane-bound reductase and enters the cell via a passive transporter. Once in the cell, copper becomes bound to copper chaperones responsible for delivering copper to specific proteins. The Wilson/Menkes ATPase accepts copper from these chaperones and pumps it into the Golgi for incorporation into various proteins such as ceruloplasmin (Cp). Ceruloplasmin may also play a role in delivering copper to peripheral tissues via cell-surface receptors that internalize the protein. The Wilson disease ATPase may also play a role in the elimination of copper into the bile...

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