This module delves into the metabolism of proteins and amino acids, a critical area for understanding physiological processes and disease states relevant to the USMLE. We'll cover digestion, absorption, synthesis, degradation, and the fate of amino acids, including their roles in energy production and the synthesis of essential biomolecules.

Proteins are large molecules that must be broken down into smaller peptides and amino acids before they can be absorbed by the body. This process begins in the stomach and continues in the small intestine, involving a cascade of enzymatic reactions.

In the stomach, pepsin, an endopeptidase, begins breaking down proteins into smaller polypeptides. The acidic environment of the stomach (pH 1.5-3.5) is optimal for pepsin activity and also denatures proteins, making them more accessible to enzymatic digestion. As the chyme moves into the small intestine, pancreatic proteases like trypsin, chymotrypsin, and carboxypeptidase further hydrolyze polypeptides into smaller peptides and free amino acids. Finally, brush border enzymes on the intestinal epithelial cells, such as aminopeptidases and dipeptidases, complete the breakdown into absorbable amino acids, dipeptides, and tripeptides.

The body synthesizes non-essential amino acids from other metabolic intermediates. Essential amino acids, however, must be obtained from the diet. Amino acid degradation is a complex process that involves removing the amino group, which is then converted to urea for excretion, and processing the carbon skeleton for energy production or biosynthesis.

The urea cycle is a crucial metabolic pathway occurring primarily in the liver that detoxifies ammonia by converting it into urea. This cycle is essential for preventing ammonia toxicity, which can lead to severe neurological damage.

The urea cycle begins in the mitochondria with the condensation of ammonia and bicarbonate to form carbamoyl phosphate, catalyzed by carbamoyl phosphate synthetase I (CPS I), which requires N-acetylglutamate as an allosteric activator. Carbamoyl phosphate then condenses with ornithine to form citrulline, which is transported to the cytosol. In the cytosol, citrulline reacts with aspartate to form argininosuccinate. Argininosuccinate is cleaved to yield fumarate and arginine. Finally, arginase hydrolyzes arginine to produce urea and ornithine, which re-enters the cycle. Fumarate can enter the citric acid cycle.

Amino acids are not primarily used for energy, but their carbon skeletons can be catabolized to generate ATP, especially during prolonged fasting or starvation when glucose is scarce. The fate of the carbon skeleton determines whether an amino acid is glucogenic (can be converted to glucose) or ketogenic (can be converted to acetyl-CoA or acetoacetyl-CoA).

The human body can synthesize 11 of the 20 standard amino acids, known as non-essential amino acids. These are synthesized from intermediates of glycolysis, the citric acid cycle, and the pentose phosphate pathway. This synthesis is vital for maintaining protein homeostasis and providing precursors for other biomolecules.

Understanding protein and amino acid metabolism is crucial for several clinical scenarios tested on the USMLE. Key areas include inborn errors of metabolism (e.g., phenylketonuria, urea cycle disorders), nutritional deficiencies (e.g., kwashiorkor, marasmus), and the metabolic consequences of liver disease.

Phenylketonuria (PKU) is an autosomal recessive disorder caused by a deficiency in the enzyme phenylalanine hydroxylase, which converts phenylalanine to tyrosine. This leads to the buildup of phenylalanine and its toxic byproducts, causing severe intellectual disability if untreated. Dietary restriction of phenylalanine is the cornerstone of management. Maple syrup urine disease (MSUD) is another example, characterized by the inability to metabolize branched-chain amino acids (leucine, isoleucine, valine), leading to their accumulation and neurological damage. Liver disease can impair urea cycle function, leading to hyperammonemia and hepatic encephalopathy.