Glycolysis and Gluconeogenesis

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The first metabolic pathway that we encounter is glycolysis, an ancient pathway employed by a host of organisms. Glycolysis is the sequence of reactions that metabolizes one molecule of glucose to two molecules of pyruvate with the concomitant net production of two molecules of ATP. This process is anaerobic (i.e., it does not require O₂) because it evolved before substantial amounts of oxygen accumulated in the atmosphere. Pyruvate can be further processed anaerobically to lactate (lactic acid fermentation) or ethanol (alcoholic fermentation). Under aerobic conditions, pyruvate can be completely oxidized to CO₂, generating much more ATP, as will be described in chapters 17 and 18. Figure 16.1 shows some possible fates of pyruvate produced by glycolysis.

Because glucose is such a precious fuel, metabolic products, such as pyruvate and lactate, are salvaged to synthesize glucose in the process of gluconeogenesis. Although glycolysis and gluconeogenesis have some enzymes in common, the two pathways are not simply the reverse of each other. In particular, the highly exergonic, irreversible steps of glycolysis are bypassed in gluconeogenesis. The two pathways are reciprocally regulated so that glycolysis and gluconeogenesis do not take place simultaneously in the same cell to a significant extent.

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Our understanding of glucose metabolism, especially glycolysis, has a rich history. Indeed, the development of biochemistry and the delineation of glycolysis went hand in hand. A key discovery was made by Hans and Eduard Buchner in 1897, quite by accident. The Buchners were interested in manufacturing cell-free extracts of yeast for possible therapeutic use. These extracts had to be preserved without the use of antiseptics such as phenol, and so they decided to try sucrose, a commonly used preservative in kitchen chemistry. They obtained a startling result: sucrose was rapidly fermented into alcohol by the yeast juice. The significance of this finding was immense. The Buchners demonstrated for the first time that fermentation could take place outside living cells. The accepted view of their day, asserted by Louis Pasteur in 1860, was that fermentation is inextricably tied to living cells. The chance discovery by the Buchners refuted this dogma and opened the door to modern biochemistry. The Buchners’ discovery inspired the search for the biochemicals that catalyze the conversion of sucrose into alcohol. The study of metabolism became the study of chemistry.

Studies of muscle extracts then showed that many of the reactions of lactic acid fermentation were the same as those of alcoholic fermentation. This exciting discovery revealed an underlying unity in biochemistry. The complete glycolytic pathway was elucidated by 1940. Glycolysis is also known as the Embden–Meyerhof pathway, after two pioneers of research on glycolysis.

We typically consume in our diets a generous amount of starch and a smaller amount of glycogen. These complex carbohydrates must be converted into simpler carbohydrates for absorption by the intestine and transport in the blood. Starch and glycogen are digested primarily by the pancreatic enzyme α-amylase and to a lesser extent by salivary α-amylase. Amylase cleaves the α-1,4 bonds of starch and glycogen, but not the α-1,6 bonds. The products are the di- and trisaccharides maltose and maltotriose. The material not digestible because of the α-1,6 bonds is called the limit dextrin.

Maltase cleaves maltose into two glucose molecules, whereas α-glucosidase digests maltotriose and any other oligosaccharides that may have escaped digestion by the amylase. α-Dextrinase further digests the limit dextrin. Maltase and α-glucosidase are located on the surface of the intestinal cells, as is sucrase, an enzyme that degrades the sucrose contributed by vegetables to fructose and glucose. The enzyme lactase is responsible for degrading the milk sugar lactose into glucose and galactose. The monosaccharides are transported into the cells lining the intestine and then into the bloodstream.

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Glucose is a common and important fuel. In mammals, glucose is the only fuel that the brain uses under nonstarvation conditions and the only fuel that red blood cells can use at all. Indeed, almost all organisms use glucose, and most that do process it in a similar fashion. Recall from Chapter 11 that there are many carbohydrates. Why is glucose instead of some other monosaccharide such a prominent fuel? We can speculate on the reasons. First, glucose is one of several monosaccharides formed from formaldehyde under prebiotic conditions, and so it may have been available as a fuel source for primitive biochemical systems. Second, glucose has a low tendency, relative to other monosaccharides, to nonenzymatically glycosylate proteins. In their open-chain forms, monosaccharides contain carbonyl groups that can react with the amino groups of proteins to form Schiff bases, which rearrange to form a more stable amino–ketone linkage. Such nonspecifically modified proteins often do not function effectively. Glucose has a strong tendency to exist in the ring conformation and, consequently, relatively little tendency to modify proteins. Recall that all the hydroxyl groups in the ring conformation of β-glucose are equatorial, contributing to the sugar’s high relative stability.