Bioenergetic Pathways

Injury affects one or more of the individual steps of these pathways in ways that will become apparent later. Even if an injury primarily affects a single step in a single pathway, the biochemical lesion is soon reflected in several more steps and in other pathways. Proper interpretation of the various biochemical alterations that result from a primary injury requires detailed knowledge of all main and alternative pathways and their enzymes and coenzymes. 

In the next part of this book, the intracellular localization of some of the most important metabolic functions is discussed. These functions can be divided into three 

Glucose is an important source of energy and building blocks. In mammalian tissue, it is degraded essentially in four metabolic pathways glycolysis, the hexose monophosphate shunt, the tricarboxylic acid cycle, and the uronic cycle. 

Inasmuch as insulin facilitates the cell s utilization of glucose, it seems logical to introduce the study of glycolysis by analyzing the mode of action of insulin on glucose utilization. However, insulin s mode of action is so closely connected with studies on diabetes that the description of the hormone s mechanism of action is deferred to the section on diabetes. 

Glucose can enter metabolism only through its conversion to glucose-6-phosphate. Hexokinase is the enzyme catalyzing that reaction at the expense of ATP [30-32]. 

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A search for organisms with novel metabolic and bioenergetic pathways, particularly pathways involved in carbon dioxide and carbon monoxide reduction and methane oxidation coupled with electron acceptors other than oxygen ... 

Biochemists have demonstrated at least 80 different enzymes in preparations of nuclei. Among them are enzymes of the main bioenergetic pathways and a large number of hydrolytic enzymes. On the basis of their relationship to the nucleus, the enzymes in nuclear preparations can be divided into three different groups (1) those likely to be contaminants (2) those clearly related to the nucleus and (3) those present in the nucleus. 

Several metabolic blocks could account for the biochemical distortion observed in maple syrup disease. A deficiency in amino oxidase could lead to accumulation of amino acids. Because the enzyme has such a broad specificity, whenever it is completely deleted a more complex aminoaciduria can be expected to develop. The deletion of a specific transaminase could hardly explain the keto acid accumulation. Therefore, it seems more likely that the metabolic block involves a step between the keto acid and the simple acids, possibly the oxidative decarboxylation of the keto acid. This reaction requires coenzyme A, NAD, lipoic acid, and thiamine pyrophosphate, and it was described in some detail in the chapter devoted to the bioenergetic pathways. Leukocytes of at least some patients with maple syrup disease have been shown to contain normal transaminase activity but are defective in the oxidative decarboxylase. 

The egg and the embryonic cell are well endowed with bioenergetic pathways. The multiple-enzyme systems involved in glycolysis, the hexose monophosphate shunt, the Krebs cycle, the electron transport chain, and oxidative phosphorylation have all been found in the vertebrate embryo. In the embryonic and in the mature cell, oxidation through the Krebs cycle, electron transport, and coupling of oxidation and phosphorylation occur in mitochondria. The chemical energy provided by these pathways is needed for normal development because if either glycolysis, Krebs cycle, or electron transport chain inhibitors are administered in vivo or added to explanted chick or sea urchin embryos, embryonic development is arrested. 

The postnatal development of alkaline phosphatase in the intestinal mucosa of rats and mice is similar to that of tryptophan pyrrolase. Much work in mammalian developmental biochemistry was done on developing liver. Studies on prenatal liver include investigations on the bioenergetic pathways and studies of the formation of enzyme found exclusively in liver. Burch [13] measured the activity of several enzymes involved in glycolysis, the hexose monophosphate shunt, glycogenolysis, and gluconeogenesis. The results of these studies show that the biochemical development of the liver can be divided into three periods prenatal, from 0 to 21 days, and after 21 days. 

Saliva is a hypotonic, slightly acid, watery excretion of the salivary gland. Man excretes 1 ml of saliva per minute, about 1,000-1,500 ml daily. The submaxillary gland is responsible for 10% of salivary secretion, the parotid only for 25%, and the sublingual for approximately 5%. Saliva secretion is blocked by metabolic inhibitors that interfere with the bioenergetic pathways, and is therefore believed to be an active process. 

The difference between the enzyme compositons of the reticulocyte and the erythrocyte will become more apparent if we briefly consider the enzyme composition of the erythrocyte. The erythrocyte seems to have lost most of its biosynthetic pathway. Indeed, it no longer makes DNA, RNA, and proteins. Even its bioenergetic pathways seem to have been reduced to the bare mini-... 

These studies raise two problems (1) what is the primary lesion responsible for the chain of biochemical alterations and, (2) are the biochemical injuries responsible for the histological alterations observed after steroid administration Since the effect of steroid on respiration does not correlate with its effect on the glycine incorporation in proteins and nucleic acids, the primary effect of the steroid appears to be interference with the bioenergetic pathway, possibly by inhibiting the utilization of glucose by lymphocytes. 

It was suggested above that steroid hormones act by stimulating bioenergetic pathways, and that as a result of this stimulation, the biosynthesis of phospholipids, proteins, and nucleic acids is activated. After estrogen administration there is a rapid uptake of precursors P in phospholipids, glycine or other amino acids into proteins, and serine and formate into the purine and pyrimidines of the nucleic acid. 

Nevertheless, the sequence of events in the uteri of estrogen-stimulated animals argues against a primary effect of the hormone on the bioenergetic pathway because the changes in the increase in the rate of biosynthesis—especially that of proteins—usually precede the changes in the rate of respiration. An alternative hypothesis suggests that the primary effect of the steroid hormone is on protein biosynthesis. 

During the lag period the hormone is bound, and activity in the bioenergetic pathway is increased. Whether aldosterone acts by stimulating the bioenergetic pathway or by modifying the permeability of the membrane to sodium remains to be established. Aldosterone was first believed to affect only the distal... 

Whereas sodium participates in metabolism mainly by its cationic properties, potassium is more directly involved in metabolism. Potassium stimulates the activity of a specific enzyme— pyruvic kinase—and is required for the phosphorylation of fructose-1-phosphate to fructose-1,6-diphosphate. Similarly, potassium stimulates acetyl kinase activity. Many alterations in the bioenergetic pathways of the cell are accompanied by changes in the intracellular concentration of potassium. After insulin administration, some of the potassium of the extracellular fluid is transferred inside the cells. During oxidative phosphorylation, potassium accumulates inside the mitochondria, and dinitrophenol uncouples the ion penetration and the oxidation. 

Hippier, M., Redding, K., and Rochaix, J.-D., Chlamydomonas genetics, a tool for the study of bioenergetic pathways, Biochim. Biophys. Acta, 1367, 1,1998. 

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