Membrane metabolic pathways

FIGURE 18.5 Schematic representation of types of multienzyme systems carrying out a metabolic pathway (a) Physically separate, soluble enzymes with diffusing intermediates, (b) A multienzyme complex. Substrate enters the complex, becomes covalently bound and then sequentially modified by enzymes Ei to E5 before product is released. No intermediates are free to diffuse away, (c) A membrane-bound multienzyme system. 

Although the interior of a prokaryotic cell is not subdivided into compartments by internal membranes, the cell still shows some segregation of metabolism. For example, certain metabolic pathways, such as phospholipid synthesis and oxidative phosphorylation, are localized in the plasma membrane. Also, protein biosynthesis is carried out on ribosomes. 

Since this facilitated transport system allows the equilibrium of bilirubin across the sinusoidal membrane of the hepatocyte, the net uptake of bilirubin will be dependent upon the removal of bilirubin via subsequent metabolic pathways. 

A common characteristic of metabolic pathways is that the product of one enzyme in sequence is the substrate for the next enzyme and so forth. In vivo, biocatalysis takes place in compartmentalized cellular structure as highly organized particle and membrane systems. This allows control of enzyme-catalyzed reactions. Several multienzyme systems have been studied by many researchers. They consist essentially of membrane- [104] and matrix- [105,106] bound enzymes or coupled enzymes in low water media [107]. 

Peroxisomes are single-membrane, typically spherical, organelles ranging in size from 0.1-1 pm in diameter and numbering from a few hundred to a few thousand in mammalian cells [8]. The matrix contains 50 or more enzymes that participate in various metabolic pathways particularly those involved in the [3-oxidation of straight and 2-methyl branched very-long-chain and long-chain... 

Schachter, H. (1972). The use of the steady-state assumption to derive kinetic formulations for the transport of a solute across a membrane. In Metabolic Transport, ed. Hokin, L. E., Metabolic Pathways. Vol. 6, Series ed. Greenberg, D. M., Academic Press, New York, pp. 1-15. 

Liver toxicity related to 1,2-dibromoethane depends on the metabolic pathway utilized and the amount of damage induced in cellular protein and membrane structures. Humans exposed to low levels of 1,2-dibromoethane are at potential risk of having toxic events occurring within hepatocytes whether these effects will be subcellular or result in cell necrosis may depend on internal dose and a variety of factors. Liver damage that is severe enough to cause clinical disease in humans from low-level exposure is unlikely. 

The membrane-associated Akt kinase is now a substrate for protein kinase PDKl that phosphorylates a specific Thr and Ser residue of Akt kinase. The double phosphorylation converts Akt kinase to the active form. It is assumed that the Akt kinase now dissociates from the membrane and phosphorylates cytosolic substrates such as glycogen synthase kinase, 6-phosphofructo-2-kinase and ribosomal protein S6 kinase, p70 . According to this mechanism, Akt kinase regulates central metabolic pathways of the cell. Furthermore, it has a promoting influence on cell division and an inhibitory influence on programmed cell death, apoptosis. A role in apoptosis is suggested by the observation that a component of the apoptotic program. Bad protein (see Chapter 15) has been identified as a substrate of Akt kinase. 

The DAG produced by the hydrolysis of PIP2 by PLC remains in the plasma membrane where it activates a family of membrane-associated protein kinases collectively termed protein kinase C (PKC). Activated PKC produces a variety of cellular responses, including the regulation of protein synthesis and key metabolic pathways. 

Synthesis of most phospholipids starts from glycerol-3-phosphate, which is formed in one step from the central metabolic pathways, and acyl-CoA, which arises in one step from activation of a fatty acid. In two acylation steps the key compound phosphatidic acid is formed. This can be converted to many other lipid compounds as well as CDP-diacylglycerol, which is a key branchpoint intermediate that can be converted to other lipids. Distinct routes to phosphatidylethanolamine and phosphatidylcholine are found in prokaryotes and eukaryotes. The pathway found in eukaryotes starts with transport across the plasma membrane of ethanolamine and/or choline. The modified derivatives of these compounds are directly condensed with diacylglycerol to form the corresponding membrane lipids. Modification of the head-groups or tail-groups on preformed lipids is a common reaction. For example, the ethanolamine of the head-group in phosphatidylethanolamine can be replaced in one step by serine or modified in 3 steps to choline. 

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