MCAT Biochemistry Review

Chapter 9: Carbohydrate Metabolism I: Glycolysis, Glycogen, Gluconeogenesis, and the Pentose Phosphate Pathway

9.5 Glycogenesis and Glycogenolysis

Glycogen, a branched polymer of glucose, represents a storage form of glucose. Glycogen synthesis and degradation occur primarily in liver and skeletal muscle, although other tissues store smaller quantities. Glycogen is stored in the cytoplasm as granules. Each granule has a central protein core with polyglucose chains radiating outward to form a sphere, as shown in Figure 9.7. Glycogen granules composed entirely of linear chains have the highest density of glucose near the core. If the chains are branched, the glucose density is highest at the periphery of the granule, allowing more rapid release of glucose on demand.

Figure 9.7. A Glycogen Granule


The glycogen in the liver and in skeletal muscle serve two quite different roles. Liver glycogen is broken down to maintain a constant level of glucose in the blood; muscle glycogen is broken down to provide glucose to the muscle during vigorous exercise.

Glycogen stored in the liver is a source of glucose that is mobilized between meals to prevent low blood sugar, whereas muscle glycogen is stored as an energy reserve for muscle contraction.

While our focus is on human metabolism, it is worth mentioning that plants also store excess glucose in long α-linked chains of glucose called starch, as seen in Figure 9.8.

Figure 9.8. Potatoes and Potato Starch


Glycogenesis is the synthesis of glycogen granules. It begins with a core protein called glycogenin. As shown in Figure 9.9, glucose addition to a granule begins with glucose 6-phosphate, which is converted to glucose 1-phosphate. This glucose 1-phosphate is then activated by coupling to a molecule of uridine diphosphate (UDP), which permits its integration into the glycogen chain by glycogen synthase. This activation occurs when glucose 1-phosphate interacts with uridine triphosphate (UTP), forming UDP-glucose and a pyrophosphate (PPi).

Figure 9.9. Glycogen Metabolism

Glycogen Synthase

Glycogen synthase is the rate-limiting enzyme of glycogen synthesis and forms the α-1,4 glycosidic bond found in the linear glucose chains of the granule. It is stimulated by glucose 6-phosphate and insulin. It is inhibited by epinephrine and glucagon through a protein kinase cascade that phosphorylates and inactivates the enzyme.

Branching Enzyme (Glycosyl α-1,4:α-1,6 Transferase)

Branching enzyme is responsible for introducing α-1,6-linked branches into the granule as it grows. The process by which the branch is introduced is shown schematically in Figure 9.10. Branching enzyme:

·        Hydrolyzes one of the α-1,4 bonds to release a block of oligoglucose (a few glucose molecules bound together in a chain), which is then moved and added in a slightly different location.

·        Forms an α-1,6 bond to create a branch.

Figure 9.10. Branching Enzyme


α-1,4 keeps the same branch moving “4ward”; α-1,6 (one-six) “puts a branch in the mix.”


The rate-limiting enzyme of glycogenolysis, the process of breaking down glycogen, is glycogen phosphorylase. In contrast to a hydrolase, a phosphorylase breaks bonds using an inorganic phosphate instead of water. The glucose 1-phosphate formed by glycogen phosphorylase is converted to glucose 6-phosphate by the same mutase used in glycogen synthesis, as shown in Figure 9.9.


Under the pressure of Test Day, it can be easy to misread words. When given a passage or question about carbohydrate metabolism, be sure you focus so you can distinguish between glycolysisglycogenesisglycogenolysis, and gluconeogenesis.

Glycogen Phosphorylase

Glycogen phosphorylase breaks α-1,4 glycosidic bonds, releasing glucose 1-phosphate from the periphery of the granule. It cannot break α-1,6 bonds and therefore stops when it nears the outermost branch points. Glycogen phosphorylase is activated by glucagon in the liver, so that glucose can be provided for the rest of the body. In skeletal muscle, it is activated by AMP and epinephrine, which signal that the muscle is active and requires more glucose. It is inhibited by ATP.

Debranching Enzyme (Glucosyl α-1,4:α-1,4 Transferase and α-1,6 Glucosidase)

Debranching enzyme is a two-enzyme complex that deconstructs the branches in glycogen that have been exposed by glycogen phosphorylase. The two-step process by which this occurs is diagrammed in Figure 9.11. Debranching enzyme:

·        Breaks an α-1,4 bond adjacent to the branch point and moves the small oligoglucose chain that is released to the exposed end of the other chain.

·        Forms a new α-1,4 bond.

·        Hydrolyzes the α-1,6 bond, releasing the single residue at the branch point as free glucose. This represents the only free glucose produced directly in glycogenolysis (as opposed to the glucose produced from glucose 1-phosphate, which must be converted by a mutase to glucose 6-phosphate before it can be converted to glucose via the enzyme glucose 6-phosphatase).

Figure 9.11. Debranching Enzyme


Debranching enzyme is actually made up of two enzymes with different functions: one moves the terminal end of a glycogen chain to the branch point (α-1,4:α-1,4 transferase), and one removes the glucose monomer actually present at the branch point (α-1,6 glucosidase).


There are a number of genetic deficiencies that can impact the metabolism of glycogen. The clinical features of a metabolic glycogen defect depend on a few important factors: which enzyme is affected, the degree to which that enzyme's activity is decreased, and which isoform of the enzyme is affected. Isoforms are slightly different versions of the same protein; in the case of glycogen enzymes, there are often different isoforms of the enzymes in the liver and muscle. These deficiencies are termed glycogen storage diseases because all are characterized by accumulation of glycogen in one or more tissues.


The most common glycogen storage disease is von Gierke's disease, a defect in glucose-6-phosphatase. Because this enzyme is also the last step of gluconeogenesis, this process is also affected, leading to periods of extremely low blood sugar between meals. These patients therefore need continuous feeding with carbohydrates to maintain blood sugar. With the buildup of glucose 6-phosphate in liver cells, the liver enlarges and is damaged over time.

MCAT Concept Check 9.5:

Before you move on, assess your understanding of the material with these questions.

1.    What is the structure of glycogen? What types of glycosidic links exist in a glycogen granule?

2.    What are the two main enzymes of glycogenesis, and what does each accomplish?



3.    What are the two main enzymes of glycogenolysis, and what does each accomplish?