Protein Catabolism Notes

Protein Catabolism

Conditions Causing Protein Catabolism

Several conditions can lead to protein catabolism:

• Age: As living organisms age, cell replacement occurs, involving the breakdown of damaged or dead cells.
• Illness: When living organisms are sick, their bodies may break down protein.
• Nutrient Deficiency: Insufficient nutrient intake.
• Unbalanced Nutrition: An imbalance in nutrient intake.
• Amino Acid (AA) Deficiency

Protein catabolism primarily occurs in the liver and tissues. Proteins, as polypeptides, are broken down into oligopeptides, which are further broken down into amino acids and their derivatives. Amino acids undergo deamination, producing ammonia, urea, and alpha-keto acids, which are converted into $CO_2$ and energy (ATP). These simpler forms then serve as fuel for anabolic reactions.

Protein Breakdown and Amino Acid Fate

Proteins are broken down by protease enzymes into amino acids and their derivatives, which can then be transported into cells through the cell membrane. These amino acids can then be polymerized into new proteins via RNA and ribosomes.

Amino acids can be recycled, forming new amino acids through transamination, or they can be converted through the Krebs cycle.

Amino Acid Pool and Sources

Digested food is broken down into amino acids in the digestive system. These amino acids are absorbed through the intestinal walls and transported to the liver, where they undergo anabolism to form proteins. Unused amino acids are transported to the "amino acid pool" in the blood.

The blood serves as an "amino acid pool," which receives amino acids from three sources:

• Absorption through the intestinal walls as a result of food digestion.
• Protein catabolism within cells.
• Amino acid anabolism within cells.

Pathway of Nitrogen/Protein Catabolism

The pathway of nitrogen/protein catabolism in the body involves:

• Breaking down proteins (both from the body and from consumed rations) into amino acid units.
• Amino acids undergo transamination (transfer of amino groups).
• Amino acids undergo oxidative deamination, releasing the amino group. The amino group enters the urea cycle, and the alpha-keto acid enters the citric acid cycle (Krebs cycle) to produce energy.

Energy Conversion

To convert proteins into energy released amino groups via deamination. The remaining molecule then proceeds through the Krebs Cycle / Citric Acid Cycle (TCA).

By entering the Citric Acid Cycle, the original protein transforms into energy usable by the organism. Other processes convert amino acids into molecules that can enter the TCA cycle, including transamination (amino group transfer), decarboxylation (carboxyl group removal), and dehydrogenation (hydrogen removal).

Protein Degradation inside Cells

Protein degradation occurs inside cells, requiring amino acids to pass through specific membranes before use. The initial step involves breaking down proteins into amino acids via proteolysis, which is cutting the peptide bonds. Proteasomes, using ATP energy, hydrolyze these peptide bonds. Enzymes called proteases further assist by breaking down remaining peptide residues into individual amino acids, ready for conversion into molecules usable for glycolysis or the TCA cycle, to generate energy or to synthesize new proteins.

Different types of proteases, such as serine, aspartate, and metalloproteases, utilize various mechanisms to cleave peptide bonds and initiate protein degradation. For example, serine proteases, like trypsin, use a nucleophilic attack on the hydroxyl oxygen of serine on the carbonyl of the peptide bond to cleave the bond. This creates an acyl-enzyme intermediate, and the mechanism continues to hydrolyze further bonds.

Catabolism Reactions

Through catabolism, proteins are broken down into amino acids. These amino acids can serve as an energy source when needed (oxidative deamination) or be recycled to create proteins or oxidized into urea (transamination).

Transamination is amino acid metabolism involving the transfer of an amino group from one amino acid to another. In this process, no amino groups are lost; instead, each released amino group is bound by a ketone compound (alpha-keto acid, which is a derivative of the amino acid after releasing its amino group).

After releasing the amino group, some amino acids become pyruvic acid, glutamic acid, and fumarate.

Transamination

Transamination example: alanine + alpha-ketoglutarate → pyruvic acid + glutamic acid.

Transamination leads to the same final result as deamination: the remaining alpha-keto acid undergoes glycolysis or the TCA cycle to produce energy for the organism's needs. This process transfers the amino group to alpha-ketoglutarate, converting it into glutamate, which can then transfer the amino group to oxaloacetate. This transfer enables oxaloacetate to be converted into aspartate or another amino acid. Eventually, these products also proceed to oxidative deamination, once again producing alpha-ketoglutarate, the alpha-keto acid for the TCA cycle, and ammonium, which will undergo the urea cycle.

Oxidative Deamination

Oxidative deamination is a chemical reaction that releases an amino group. The released amino group becomes an ammonia ion ($NH_4$+), entering the urea cycle in the liver. This process produces urea, which is then excreted through the kidneys via urine.

Deamination products that can enter the Krebs cycle include alpha-keto-glutarate, succinyl-CoA, fumarate, oxaloacetate, and citrate.

Deamination reaction: amino acid + $NAD^+$ → keto acid + $NH<em>3$. Ammonia ($NH</em>3$) is toxic to the body and can poison the brain, leading to a coma. Because the kidneys cannot excrete ammonia directly, it must first be converted into urea through the urea cycle in the liver. Liver dysfunction impairs this conversion, causing a buildup of $NH_3$ in the blood, a condition called uremia.

Amino Acid Degradation

Amino acid degradation in mammals occurs in the liver, producing $NH<em>3$ and carbon chains. Amino groups are transferred to alpha-ketoglutarate, forming glutamate, by aminotransferase enzymes. Glutamate undergoes oxidative deamination, producing $NH</em>4$+ ions, catalyzed by glutamate dehydrogenase using $NAD^+$ or $NADP^+$.

Oxidative deamination is the first step in breaking down amino acids for conversion into sugars, involving the removal of the amino group, which becomes ammonium and enters the urea cycle to become urea in the liver. Urea is then released into the bloodstream, transferred to the kidneys, and excreted as urine.

Alpha-Keto Acids

The remaining part of the amino acid (alpha-keto acid) is oxidized, entering the TCA cycle to generate energy or undergoing glycolysis to be converted into pyruvate. Pyruvate can then be converted into Acetyl-CoA to enter the TCA cycle and produce ATP.

Fate of Carbon Skeletons

After deamination, the remainder of the amino acid is called the "carbon skeleton". The fate of the carbon skeleton depends on the specific amino acid being catabolized.

It will be converted to:

• Acetyl CoA: Carbon skeletons that end up as acetyl CoA are used for energy production.

  • They are either immediately oxidized via the citric acid cycle.
  • Or, they may be converted to ketone bodies.
  • Amino acids whose carbon skeletons yield acetyl CoA are called ketogenic amino acids.

• A citric acid cycle intermediate: The carbon skeletons which end up as pyruvate or a citric acid cycle intermediate.

  • They may be used for energy production.
  • Or, they may be used to synthesis glucose by the pathway known as gluconeogenesis.
  • Amino acids whose carbon skeletons yield pyruvate or a citric acid cycle intermediate are called glucogenic amino acids.

Urea Cycle (Ornithine Cycle)

The urea cycle (also known as the ornithine cycle) is the reaction by which ammonia ($NH<em>3$) is converted into urea ($(NH</em>2)_2CO$). This chemical reaction occurs mostly in the liver and slightly in the kidneys. The liver is the center of ammonia conversion to urea, reflecting its role in neutralizing toxins.

Ammonia is a product of amino acid degradation and is toxic, posing a threat if it accumulates in the body. Since the human body cannot quickly dispose of ammonia, it is converted into the less toxic urea. The urea produced in the liver is released into the bloodstream, then filtered by the kidneys and excreted in urine. In normal conditions, urine contains between 9.3 g/l and 23.3 g/l of urea.

Stages of Urea Cycle

The conversion of ammonia to urea consists of five reaction stages: two take place in the mitochondria, and three occur in the cytoplasm.

The stages in the urea cycle are as follows:

1. Ammonia is converted to carbamoyl phosphate, with the help of carbamoyl phosphate synthetase I enzyme and using 2 ATP molecules.
2. Carbamoyl phosphate is converted to citrulline, aided by the ornithine transcarbamoylase enzyme. This enzyme combines carbamoyl phosphate with ornithine, forming citrulline and releasing a phosphate group.
3. Citrulline combines with the amino acid aspartate, forming argininosuccinate. This reaction requires ATP and is assisted by the argininosuccinate synthetase enzyme.
4. Argininosuccinate is broken down into arginine and fumarate by the argininosuccinase enzyme.
5. Arginine is broken down into urea and ornithine by the arginase enzyme. Urea is released into the bloodstream, while ornithine is used again for the urea cycle. Steps 1 and 2 occur in the mitochondria, while steps 3, 4, and 5 take place in the cytoplasm.