LEHNINGER PRINCIPLES OF BIOCHEMISTRY - VOL. 2. BIOENERGETICS AND METABOLISM - 2014

PART II. BIOENERGETICS AND METABOLISM

14. GLYCOLYSIS, GLUCONEOGENESIS, AND THE PENTOSE PHOSPHATE PATHWAY

14.2. Glycolysis Feeders

Glycolysis is not restricted to glucose alone; many other CARBOHYDRATES enter the pathway after being converted into one of the glycolytic intermediates. The most significant roles are played by the Storage Polysaccharides starch and Glycogen, the Disaccharides maltose, lactose, trehalose, and sucrose, and the Monosaccharides fructose, mannose, and galactose (Fig. 14-10).

Class="center">Fig. 14-10. Entry of dietary glycogen, starch, disaccharides, and hexoses into the preparatory stage of glycolysis.

Dietary Polysaccharides and Disaccharides Are Broken Down to Monosaccharides

For almost all people, starch serves as the primary carbohydrate source. Starch Digestion begins in the Mouth under the action of the salivary enzyme α-amylase (Fig. 14-10), which catalyzes the Hydrolysis of internal glycosidic bonds in the starch molecule, yielding shorter polysaccharide fragments or Oligosaccharides. (Note that this hydrolysis reaction involves an attack by a Water molecule rather than inorganic phosphate.) In The Stomach, salivary α-amylase is inactivated by the low pH, but another α-amylase, secreted by the Pancreas into the Small Intestine, subsequently takes over. The action of pancreatic α-amylase produces primarily maltose and maltotriose (glucose di- and trisaccharides with α1—>4 linkages), as well as so-called limit dextrins, which are amylopectin fragments containing α1—>6 linkages at branch points. Maltose and dextrins are further degraded at the intestinal brush border (microscopic projections of the intestinal epithelium that vastly increase the intestinal surface area). Dietary glycogen has a Structure largely similar to that of starch, and its breakdown follows the same pathway.

Endogenous Glycogen and Starch Are Broken Down by Phosphorolysis

Glycogen stored in animal Tissues (principally The Liver and skeletal Muscles) and microbial Cells, as well as plant starch, can be utilized directly by the cells via a phosphorolysis reaction catalyzed by Glycogen phosphorylase (or starch phosphorylase in plants). These Enzymes catalyze the attack by inorganic phosphate on the glycosidic bond (α1—>4) linking two terminal glucose residues at a nonreducing end, yielding glucose-1-phosphate and a polymer shortened by one glucose unit (Fig. 14-11). Part of The energy released during the phosphorolysis of the glycosidic bond is conserved in the form of the phosphoric acid ester glucose-1-phosphate. Glycogen phosphorylase (or starch phosphorylase) acts repeatedly until it approaches a branch point with an (α1—>6) configuration (see Fig. 7-15), where its action halts. A debranching enzyme is required to remove the branch. The mechanism and Regulation of Glycogen breakdown are discussed in more detail in Chapter 15.

Fig. 14-11. Breakdown of intracellular glycogen by glycogen phosphorylase. This enzyme catalyzes the reaction of inorganic phosphate (highlighted in pink) with the terminal glucose residue (blue) at the nonreducing end of glycogen, yielding glucose-1-phosphate and a glycogen molecule shortened by one unit. This process involves phosphorolysis rather than hydrolysis.

The glucose-1-phosphate produced by glycogen phosphorylase is converted to glucose-6-phosphate in a reversible reaction catalyzed by phosphoglucomutase:

Glucose-1-phosphate ⇄ Glucose-6-phosphate

Phosphoglucomutase operates by essentially the same mechanism as phosphoglycerate mutase (p. 78). The general term mutase is applied to enzymes that catalyze The transfer of functional groups from one position to another within the same molecule. Mutases belong to the broader class of isomerases, which facilitate the interconversion of stereoisomers as well as structural or positional isomers (see Table 6-3). The glucose-6-phosphate formed by phosphoglucomutase can enter glycolysis or another metabolic pathway, such as the Pentose Phosphate Pathway (Section 14.5).

Box 14-1. Energy Conservation during Glycogen Breakdown via Phosphorylase

Calculate the energy yield (in ATP molecules per glucose monomer unit) when glycogen is degraded by phosphorolysis rather than hydrolysis.

Solution. Phosphorolysis yields phosphorylated glucose (glucose-1-phosphate), which is subsequently converted to glucose-6-phosphate without expending cellular energy (1 ATP) that would otherwise be required to form glucose-6-phosphate from free glucose. Consequently, the preparatory stage consumes only one ATP molecule per glucose monomer unit, compared with two molecules when glycolysis begins with free glucose. In other words, The Cell saves three ATP molecules per glucose monomer unit (four ATP molecules are produced during the energy-yielding stage and one, rather than two, ATP molecules are consumed in the preparatory stage), thereby conserving one net ATP molecule for each glucose monomer.

The breakdown of dietary polysaccharides such as glycogen and starch in the gastrointestinal tract via phosphorolysis instead of hydrolysis would yield no energetic advantage, because phosphorylated sugars cannot cross the intestinal mucosal cells and must first be dephosphorylated to yield free sugars.

To enter a cell, Disaccharides must first undergo hydrolysis to monosaccharides. In the intestine, disaccharides and dextrins are hydrolyzed by enzymes bound to the intestinal epithelial surface:

The resulting monosaccharides are actively transported into the epithelial cells (see Fig. 11-44), after which they enter the bloodstream and are delivered to various tissues, where they are phosphorylated and enter The Glycolytic Pathway.

Lactose intolerance is widespread among the adult population worldwide, with the exception of people of Northern European descent and certain regions of Africa. This condition results from the complete or partial absence of intestinal lactase activity in adults. As a result, lactose is not fully digested and absorbed in the small intestine, but instead passes into the Large Intestine, where Bacteria convert it into a toxic product that causes intestinal cramps and diarrhea. The problem is further compounded by the fact that unabsorbed lactose and its metabolites increase the osmolarity of the intestinal contents, which promotes water retention. In populations where lactose intolerance is prevalent, adults consume processed dairy products treated with lactase rather than plain milk. In certain human pathologies, all or nearly all intestinal disaccharidases may be absent. Therefore, for digestive issues caused by dietary disaccharides, a specific dietary regimen is recommended. ■

Other Monosaccharides Enter Glycolysis at Various Points Along the Pathway

In most organisms, not only glucose but also other hexoses can undergo glycolysis after being converted into phosphorylated derivatives. D-Fructose, which occurs freely in many fruits and is also formed in the small intestine of vertebrates during the hydrolysis of sucrose, is phosphorylated by hexokinase:

The bulk of fructose enters glycolysis in Muscle and Kidney cells via this same pathway. A different pathway operates in the liver. The liver enzyme fructokinase catalyzes the phosphorylation of fructose not at C-6, but at C-1:

Next, fructose-1-phosphate is cleaved into glyceraldehyde and dihydroxyacetone phosphate by the action of the enzyme fructose-1-phosphate aldolase:

Dihydroxyacetone phosphate is converted into glyceraldehyde-3-phosphate by the glycolytic enzyme Triosephosphate isomerase. Glyceraldehyde is phosphorylated at the expense of ATP with the participation of triosokinase to yield glyceraldehyde-3-phosphate:

As a result, both products of fructose-1-phosphate hydrolysis enter glycolysis in the form of glyceraldehyde-3-phosphate.

D-Galactose, formed by the hydrolysis of the disaccharide lactose (milk sugar), is transported via the bloodstream from the intestine to the liver, where it is first phosphorylated at the C-1 atom at the expense of ATP by the enzyme galactokinase:

Galactose-1-phosphate is then converted into the C-4 epimer—glucose-1-phosphate—through a series of reactions in which a sugar nucleotide, uridine diphosphate (UDP; Fig. 14-12), acts as the hexose group carrier. Epimerization involves The oxidation of the -OH group at the C-4 atom to a keto group, followed by the reduction of the keto group back to an -OH group with inversion of configuration. NAD⁺ serves as the cofactor in these Oxidation and reduction reactions.

Fig. 14-12. Conversion of galactose to glucose-1-phosphate. The process proceeds with The formation of a sugar-nucleotide derivative, UDP-galactose, by the replacement of glucose-1-phosphate in UDP-glucose with galactose-1-phosphate. Subsequently, UDP-galactose is converted to UDP-glucose by the action of UDP-glucose-4-epimerase; this involves the initial oxidation of the -OH group at the C-4 atom (highlighted in pink) in the presence of NAD⁺, followed by reduction in the presence of NADH. The result of this reaction is the inversion of configuration at the C-4 atom. UDP-glucose is utilized in another cycle of the same reaction. The net result of this cycle is The conversion of galactose-1-phosphate to glucose-1-phosphate; a material balance shows that neither UDP-galactose nor UDP-glucose is consumed or produced overall.

A deficiency in any of the three enzymes operating in this sequence of reactions causes galactosemia in humans. When galactokinase is deficient, high concentrations of galactose are detected in the Blood and urine. Infants may develop cataracts due to the accumulation of the galactose metabolite galactitol in the eye lenses.

The symptoms of this disorder are moderately severe; complete exclusion of galactose from the diet provides significant relief.

Galactosemia caused by transferase deficiency is a more severe condition characterized by growth retardation, speech impairments, mental deficiency, and liver damage, which can be fatal even if galactose is excluded from the diet. Epimerase deficiency is accompanied by similar symptoms but is less severe when a strict diet is maintained. ■

D-Mannose, formed during the breakdown of various polysaccharides and Glycoproteins, is phosphorylated by hexokinase at the C-6 position:

Mannose-6-phosphate is isomerized by the enzyme phosphomannose isomerase to yield fructose-6-phosphate, an intermediate of glycolysis.

Summary of Section 14.2 Metabolic Pathways Feeding into Glycolysis

■ Storage forms of glucose—the polysaccharides glycogen and starch—enter glycolysis via a two-stage process. The phosphorolytic Cleavage of a glucose residue from the end of the polysaccharide molecule, yielding glucose-1-phosphate, is catalyzed by glycogen phosphorylase or starch phosphorylase. Phosphoglucomutase then converts glucose-1-phosphate into glucose-6-phosphate, which enters the glycolytic pathway.

■ Dietary polysaccharides and disaccharides are broken down into monosaccharides by intestinal hydrolytic enzymes; the monosaccharides then cross the intestinal Cell Membrane and are transported to the liver and other tissues.

■ Various D-hexoses, including fructose, galactose, and mannose, can also enter glycolysis after being preliminarily converted into glucose-6-phosphate, fructose-6-phosphate, or fructose-1-phosphate.

■ Two nucleotide derivatives are involved in the conversion of galactose-1-phosphate to glucose-1-phosphate: UDP-galactose and UDP-glucose. Genetic Defects in any of the three enzymes catalyzing the conversion of galactose to glucose-1-phosphate cause galactosemia of varying severity.