3.0 Glycolysis, gluconeogenesis, glycogen and metabolism

In GI 2 we defined metabolism as the breakdown (catabolism) and synthesis (anabolism) of biochemical compounds occurring through separate enzymatic routes

We defined catabolism as the production of cellular energy in the form of ATP and reducing power in the form of NADH, FADH2 or NADPH.

Anabolism consumes this reducing power and ATP to build new molecules

Within the body, we observe a continual switching between catabolic

and anabolic pathways in order to maintain homeostasis.

A key element in this metabolic switching is a reciprocal regulation of opposed pathways catalysing opposing processes.

In this learning pack, we will consider the process of glucose breakdown and it's de novo synthesis and appreciate their reciprocal regulation. 

It is useful to think of glucose metabolism as linked reactions occurring in blocks,

It is useful to think of glucose metabolism as linked reactions occurring in blocks,

Each block generates molecules that are then required for the next block,

untimely generating energy (ATP) through aerobic catabolism in the Citric Acid Cycle.

The process is started through carbohydrate digestion in the GI tract, which results in free circulating glucose,

that in turn is up taken into cells allowing for it's metabolism, which we term as glycolysis. 

The primary step in glycolysis is the phosphorylation of glucose by hexokinase and glucokinase

This step results in he formation of  glucose-6-phosphate (G-6-P), which is able to inhibit hexokinase but not glucokinase

This phosphorylation step is essential in order to prevent diffusion of glucose back outside the cell. 

hese two enzymes show activity at differing concentration of fasting blood glucose:

• Hexokinase, which is broadly expressed throughout the body, including the liver, shows a high affinity for glucose (low Km),  that highlights it as the metabolic enzyme for maintenance  of background and average blood glucose. It's rate of reaction is limited due to its inhibition by G-6-P.

• Glucokinase, which is only expressed in the liver and the β-cell of the pancreas,  shows a much lower affinity for glucose (high Km), indicating activity only when high levels of blood glucose are present. As it is not rate limited by G-6-P, Glucokinase will remain metabolising glucose even as G-6-P accumulates in the liver cells and is therefore crucial during glucose spikes. In pancreatic cells glucokinase ultimately results in the release of insulin. 

G-6-P then is then either:

1. Biosynthesised into Glycogen

2. Metabolised via the Pentose Phosphate pathway to generated NADPH

3. Metabolised to generate pyruvate via glycolysis to informs the citric acid cycle, ultimately generating lactate

xcess glucose is stored in skeletal muscle cells and the liver in the form of glycogen. Glycogen is a polymer of glucose, where individual glucose molecules are linked, in branching form, through glyosidic bonds

Glycogen is converted to glucose by glycogenolysis, which is triggered by hormones like glucagon and epinephrine

Glycolysis is the anaerobic breakdown of glucose into 2 molecules of pyruvate, generating, by this process alone, energy to the cell in the form of 2 ATP, 2 NADH, and 2 pyruvates per molecule of glucose.

Glycolysis consists of 10 individual reactions (see Figure 8). While a total of 4 molecules of ATP are produced by glycolysis (Steps 7 & 10), the reaction also uses two molecules of ATP (Steps 1 & 3), resulting in a net production of two molecules of ATP. 

PFK-1 catalyses step 3 of the glycolysis reaction and is allosterically inhibited by ATP and activated by both ADP and AMP.

Therefore, when a cell requires energy and has low levels of ATP and concomitant increase in ADP and AMP, the rate of this reaction will increase. 

PFK-1 is also allosterically activated by fructose-2,6-bisphosphate,

ts synesis regulated by the enzyme PFK-2.

PFK-2 activity is increased when the ratio of insulin (released by high glucose levels) to glucagon (released by low glucose levels)

PFK-2 activity is increased when the ratio of insulin (released by high glucose levels) to glucagon (released by low glucose levels)

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Gluconeogenesis is a metabolic process by which the liver produces glucose from non-carbohydrate sources, such as fats and proteins that occurs in the liver and kidneys.

This helps maintain blood glucose levels, especially when the body's normal glucose sources aren’t sufficient to power ongoing processes, e.g. in strenuous exercise and starvation

Gluconeogenesis could be defined as the reverse process of glycolysis.

However, while similar, these are not exact, as three essentially irreversible steps of glycolysis, those catalysed by pyruvate kinase, phosphofructokinase, and hexokinase are bypassed using different enzymes in gluconeogenesis.

The Cori cycle explains the movement of lactate from skeletal muscle to the liver, where glucose is formed, that is then moved back to skeletal muscle. Much of the lactate produced by muscles in a 24 hr period is recycled in this manner

A key element of these opposing cycle is a process known as reciprocal regulation where a processes opposing pathway is down-regulated to prevent what are called futile cycles.

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The rate of gluconeogenesis is strongly controlled by circulating levels of the hormones glucagon, insulin and cortisol. Conditions characterized by imbalances in these hormones

can cause hypoglycaemia, (insulinomas, ethanol ingestion), or an accelerated gluconeogenesis and accompanying hyperglycaemia (diabetes, Cushing syndrome). Chronic hyperglycaemia leads to diabetic retinopathy, nephropathy, neuropathy, and cataracts.

Genetic disorders of glucose metabolism

These are rare diseases, where changes in the expression of certain enzymes due to changes in patient DNA sequences, result in severe clinical presentations