Anabolic Reactions of Energy Metabolism: Lecture Notes

The Anabolic Reactions of Energy Metabolism

Storing Energy

Cells obtain energy by metabolizing glucose and fatty acids, which are derived from carbohydrates and lipids in our diet.
These molecules are stored as glycogen and triglycerides, respectively, until energy is required.
Glycogen and triglycerides are synthesized in the anabolic reactions of energy metabolism.

Digestion and Absorption of Carbohydrates

The carbohydrates in our diet mainly consist of starch, sugar (sucrose), and fructose.
Starch is a polymer (polysaccharide) of glucose.
After consuming starch, the enzyme amylase in the intestinal tract digests it into maltose, a disaccharide consisting of two glucose molecules.
Maltose is further digested by maltase into two glucose molecules.
Sucrose is a disaccharide composed of glucose and fructose, digested by sucrase into its constituent monosaccharides.
Glucose released during carbohydrate digestion is absorbed into intestinal epithelial cells (enterocytes) via the sodium/glucose transporter in the apical membrane.
- This transporter simultaneously transports one sodium ion (Na+) and one glucose molecule into the enterocyte.
GLUT transporters in the basolateral membrane of enterocytes then transport glucose into the bloodstream.
From the bloodstream, glucose is transported via GLUT transporters into hepatocytes (liver cells), myocytes (muscle cells), and adipocytes (fat cells).
In hepatocytes and myocytes, glucose molecules are linked to form glycogen (a polysaccharide).
In adipocytes, glucose is used to synthesize triglycerides (fat), which consist of glycerol attached to three fatty acids.
Excess carbohydrate and sugar intake can lead to obesity as glucose is converted into triglycerides.
Fructose is absorbed into enterocytes by GLUT transporters and then transported into the bloodstream.
From the bloodstream, fructose is transported mainly into hepatocytes where it is converted to glucose and then into glycogen. Some conversion also occurs in enterocytes.
Note: Dairy products contain lactose, a disaccharide of galactose and glucose, but its digestion and absorption are not discussed in this course.
Summary: Dietary carbohydrates are converted into glucose, which is stored as glycogen in muscle and liver cells, and as triglycerides in fat cells. When energy is required, glycogen is broken down into glucose, and triglycerides into fatty acids.

Impact of Insulin on Glucose Metabolism

The rise in blood glucose concentration after carbohydrate digestion triggers insulin release from pancreatic beta cells.
Insulin stimulates glucose transport into hepatocytes, myocytes, and adipocytes, as well as the conversion of glucose into glycogen and triglycerides.
In type I diabetes, beta cells fail to release insulin, leading to abnormally high blood glucose levels.
In type II diabetes, cells become resistant to insulin, failing to take up glucose effectively, also resulting in high blood glucose concentrations.

Digestion and Absorption of Lipids

In adipocytes, glucose from carbohydrates can be converted into triglycerides. Also, dietary lipids can be a source of triglycerides.
Triglycerides (TG) are a type of lipid and the main form of fat found in food and stored in fat cells.
A triglyceride molecule consists of one glycerol molecule attached to three fatty acid molecules (also known as triacylglycerol).
Fatty acids consist of a carboxylic acid group (-COOH or –COO-) attached to a long aliphatic chain of carbons (-CH2-CH2-CH2-CH2…-CH3), referred to as an acyl chain.
In humans, fatty acids typically range from 14 to 20 carbons in length, with 16 carbons (palmitic acid) being the most common.
Fatty acids without double bonds in the acyl chain are saturated, while those with double bonds are unsaturated.

Lipid Digestion and Absorption Process

Triglyceride (TG, triacylglycerol) is the main type of fat in our diet. In the intestinal tract, the enzyme lipase digests TG into monoacylglycerol and two fatty acids.
These molecules diffuse directly across the apical membrane of enterocytes.
Inside enterocytes, monoacylglycerol and fatty acids are reassembled into TG.
In the endoplasmic reticulum (ER), TG, phospholipids, and proteins are assembled into lipoprotein particles called chylomicrons.
Chylomicrons are essentially droplets of TG surrounded by a thin layer of phospholipids and a few proteins.
Chylomicrons are secreted from the ER of enterocytes into the bloodstream.
As chylomicrons circulate, lipoprotein lipase, found predominantly on the surface of adipocytes (and myocytes), digests the TG within them into glycerol and fatty acids.
This process converts chylomicrons into chylomicron remnants.
Glycerol and fatty acids released from chylomicrons are absorbed into adipocytes and reassembled into TG by acyl transferase enzymes.
Chylomicron remnants are taken up by hepatocytes (liver cells) and further digested to provide lipids that are then transported to other cells as lipoproteins.

Key Points about Lipid Metabolism

Glucose and fatty acids are the main sources of energy in the body.
Fatty acids are stored as triglycerides in adipocytes.
Fatty acids can be synthesized from glucose or obtained from dietary triglycerides.
Dietary triglycerides are absorbed in the intestinal tract, transported as chylomicrons, and eventually stored in adipocytes.

Glycogen Synthesis in Liver and Muscle Cells

Glucose is absorbed and stored in hepatocytes and myocytes as glycogen.
Glycogen consists of interconnected glucose molecules. (Detailed structure is not covered.)

Steps in Converting Glucose to Glycogen:

Hexokinase Reaction:
- The enzyme hexokinase removes a phosphate from ATP and attaches it to glucose to form glucose-6-phosphate and ADP.
Isomerase (Phosphoglucomutase) Reaction:
- An isomerase enzyme (phosphoglucomutase) shifts the phosphate from the 6th to the 1st carbon of glucose to form glucose-1-phosphate.
UDP-glucose Pyrophosphorylase Reaction:
- Glucose-1-phosphate reacts with uridine triphosphate (UTP) to form UDP-glucose (glucose attached via two phosphates to uridine).
- Two linked phosphates (pyrophosphate – PPi) are released.
- The reaction is catalyzed by UDP-glucose pyrophosphorylase.
Glycogen Synthase Reaction:
- The glucose is transferred from UDP to glycogen (the glycogen chain grows by one glucose molecule) in a reaction catalyzed by glycogen synthase.

Glycogen contains linear chains of glucose formed by α1,4 bonds and branched chains formed by α1,6 bonds. The formation of branched chains isn't covered.

Triglyceride Synthesis in Adipocytes

Glucose is converted into triglycerides in fat cells (adipocytes), and some triglyceride synthesis also occurs in the liver.
Before triglycerides are formed, glucose is first used to synthesize fatty acids.

Fatty Acid Synthesis Steps:

Hexokinase Reaction:
- Glucose reacts with ATP via hexokinase to form glucose-6-phosphate and ADP.
Glycolysis:
- Glucose-6-phosphate is broken down into glyceraldehyde-3-phosphate and dihydroxyacetone phosphate (DHAP) by glycolytic enzymes (glycolysis will be detailed later).
Glycerol-3-Phosphate Dehydrogenase Reaction:
- DHAP is reduced to glycerol-3-phosphate by glycerol-3-phosphate dehydrogenase, oxidizing NADH + H+ to NAD+.
- Glycerol-3-phosphate is used to synthesize triglycerides.
Glycolysis and Acetyl-CoA Formation:
- Glyceraldehyde-3-phosphate (and most of the DHAP) is further broken down by glycolysis into pyruvate and then acetyl-CoA.
Acetyl-CoA Carboxylase Reaction:
- Acetyl-CoA (2 carbons) reacts with bicarbonate to form malonyl-CoA (3 carbons), catalyzed by acetyl-CoA carboxylase.
- ATP is converted to ADP and phosphate (Pi) to provide energy for the reaction. CO2 is attached to acetyl-CoA.
Malonyl-ACP Formation:
- Malonyl-CoA releases CoA and binds to acyl carrier protein (ACP) to form malonyl-ACP.
- Another acetyl-CoA releases CoA and binds to fatty acid synthase (FAS) to form acetyl-FAS. ACP is part of FAS, a large protein with multiple enzymatic domains.
Acetoacetyl-ACP Formation:
- The acetyl group is transferred to malonyl-ACP, which loses a COOH group in the form of carbon dioxide (CO2).
- The 2 carbons of the acetyl group and 3 carbons of the malonyl group combine to form a 4-carbon molecule, acetoacetyl-ACP.

Further Steps in Fatty Acid Synthesis:

The next three reactions remove the oxygen on the 3rd carbon of acetoactyl-ACP (C=O) to gradually build a fatty acid chain.

Reduction of Keto Group: The keto group (C=O) of acetoacetyl-ACP is reduced to an hydroxyl group (CH-OH) to form hydroxybutyryl-ACP. NADPH + H+ is used, transferring two electrons and oxidizing to NADP+.
Dehydration: The hydroxyl group is removed from hydroxybutyryl-ACP in the form of water (dehydration reaction) to form crotonyl-ACP.
Reduction of Double Bond: The double bond of crotonyl-ACP is reduced to a single bond by NADPH + H+ (oxidized to NADP+ in the process) to form butyryl-ACP, which is then released from ACP as butyryl-CoA.

Formation of Palmitic Acid:

These reactions form a 4-carbon fatty acid (butyric acid) attached to CoA. The most common fatty acid in triglycerides contains 16 carbons (palmitic acid).
To extend butyric acid to palmitic acid, the previous reactions repeat themselves:
1. Butyryl-CoA binds to fatty acid synthase, and malonyl-CoA (formed from acetyl-CoA) binds to ACP.
2. Butyryl-FAS and malonyl-ACP combine and release CO2 to form a 6-carbon chain attached to ACP.
3. The carbonyl (C=O) group is reduced in three reactions to remove water, converting 2 NADPH + H+ molecules to NAP+.
4. Reacting with malonyl-CoA and repeating the above reactions 5 more times forms a 16-carbon fatty acid (palmitic acid, or palmityl-CoA).
Palmityl-CoA can then be used for triglyceride synthesis.
Summary: Starting with acetyl-CoA, there are 7 cycles where it reacts with malonyl-CoA to form palmityl-CoA. Malonyl-CoA is synthesized from acetyl-CoA, which is formed during glycolysis as a breakdown product of glucose.
The reaction to synthesize palmitic acid from glucose can be summarized as:
- $8 ewline ewline ewline Acetyl-CoA + 7ATP +14NADPH + H^+ + 7HCO3^- \rightarrow Palmitic ewline ewline ewline acid + 7ADP + Pi + 14NADP^+ + 7CO2$
- Or, from glucose:
- $4 ewline ewline ewline Glucose + 7ATP +14NADPH + H^+ + 7HCO3^- \rightarrow Palmitic ewline ewline ewline acid + 7ADP + Pi + 14NADP^+ + 7CO2$

Triglyceride Synthesis: Attaching Fatty Acids to Glycerol

After fatty acids are synthesized from glucose, they are attached to glycerol to form triglycerides.

Steps:

Glycerol-3-phosphate (synthesized from glucose via DHAP) is used for TG synthesis.
A fatty acid (acyl group) is transferred from CoA (acyl-CoA) to the 1st carbon of glycerol-3-phosphate to form acylglycerol-3-phosphate, catalyzed by an acyl transferase.
The reaction repeats to attach a fatty acid to the 2nd carbon, forming diacylglycerol-3-phosphate.
To attach a fatty acid to the 3rd carbon, the phosphate group of the glycerol molecule must first be removed by a phosphatase enzyme, forming diacylglycerol.
The final fatty acid is attached to glycerol to form a triacylglycerol (triglyceride).

Glucose is now completely converted to fat, which is stored and can later be broken down as a source of energy.
Diacylglycerol-3-phosphate is also known as phosphatidic acid.

Adipocytes and Triglyceride Storage

Triglycerides form large and numerous fat droplets in the adipocyte cell cytoplasm. (Fat is insoluble in water.)

Fructose to Glucose Conversion in Liver and Enterocytes

The main carbohydrate in most diets is starch, broken down into glucose. The main sugar is sucrose, which consists of glucose and fructose. Fructose is also found in fruits, juices, and processed foods.

Fructose Conversion Process

Fructose is converted into glucose, which is then stored as glycogen and triglycerides.
This conversion occurs in liver cells and enterocytes while fructose is absorbed from the intestinal tract.

Reactions of Fructose to Glucose Conversion:

Fructokinase removes a phosphate from ATP and attaches it to the 1st carbon of fructose to form fructose-1-phosphate and ADP.
Aldolase splits fructose-1-phosphate into dihydroxyacetone phosphate (DHAP) and glyceraldehyde.
Glyceraldehyde kinase removes a phosphate from ATP and attaches it to glyceraldehyde to form glyceraldehyde-3-phosphate and ADP.
Aldolase then recombines the two molecules to form fructose-1,6-bisphosphate.
The phosphate is removed from the 1st carbon to form fructose-6-phosphate by fructose bisphosphatase.
An isomerase enzyme rearranges the bonds in fructose-6-phosphate to form glucose-6-phosphate.

Further Metabolism of Glucose-6-Phosphate

In liver cells, glucose-6-phosphate is used to synthesize glycogen in three additional steps.
In enterocytes, glucose-6-phosphatase removes the phosphate to form glucose, which is then transported into the bloodstream.
This glucose is taken up by liver and muscle cells, which reconvert it to glucose-6-phosphate for glycogen synthesis, or by fat cells, which use the glucose for triglyceride synthesis.

Efficiency of Fructose Metabolism

Glucose is converted to glucose-6-phosphate in one step using hexokinase, whereas conversion of fructose to fructose-6-phosphate requires five steps.
This complexity suggests that cells make do with the tools they have available, which may not always be optimal means for achieving things, a sign of evolution.

Summary of Energy Metabolism

The two main molecules providing cells with energy are glucose and fatty acids (glucose being particularly important in brain and neuron function).
Glucose is obtained from carbohydrates and can be used to synthesize fatty acids and store them as triglycerides in adipocytes. In liver and muscle cells, glucose is stored as glycogen.
Triglycerides in adipocytes can be synthesized from excess glucose or obtained from dietary triglycerides, which are broken down, resynthesized in enterocytes, and transported to adipocytes as chylomicrons.

Storage and Breakdown of Energy Reserves

Once formed and stored, glycogen and triglycerides can be broken down back to glucose and fatty acids when energy is required.
If glucose is not obtained from carbohydrates, it can be synthesized from amino acids obtained by breaking down proteins.

Post-Meal Sleepiness

Sleepiness after a large meal may be a means to force rest while food is converted to glycogen and triglycerides, which are needed as energy sources when food isn't available.