Protein digestion in the stomach
Dietary protein hydrolysis begins in the stomach. Chief cells secrete pepsinogen, while parietal cells secrete hydrochloric acid. HCl plays a dual role: it denatures proteins, making peptide bonds accessible, and activates pepsinogen via partial proteolysis into active pepsin. The optimal pH for pepsin is 1.5–2.0. Under its action, proteins are broken down into large peptides that pass into the duodenum.
Pancreatic proteases and their activation
The pancreas secretes proteolytic enzymes as proenzymes (zymogens) to protect itself from autodigestion: trypsinogen, chymotrypsinogen, procarboxypeptidases A and B, and proelastase.
Activation cascade:
- Enteropeptidase (enterokinase) of the small intestine brush border cleaves a hexapeptide from trypsinogen, converting it into trypsin.
- Trypsin autocatalytically activates new trypsinogen molecules and converts chymotrypsin, elastase, and carboxypeptidases A and B into their active forms.
Trypsin and chymotrypsin are endopeptidases that cleave internal peptide bonds; carboxypeptidases are exopeptidases that cleave C-terminal amino acids. This results in di- and tripeptides, which are hydrolyzed by enterocyte aminopeptidases and dipeptidases into free amino acids that are absorbed into the bloodstream.
Acute pancreatitis and trypsin inhibitors
Premature (intra-pancreatic) activation of zymogens leads to autodigestion of the pancreatic tissue, resulting in acute pancreatitis accompanied by inflammation and edema. Therapy includes protease inhibitors—Contrical, Trasylol, Gordox (aprotinin). Their efficacy is explained by the pivotal role of trypsin: blocking trypsin halts the entire activation cascade of the other proteases.
Transamination reactions
Transamination is the reversible transfer of an α-amino group from an amino acid to an α-keto acid, forming a new amino acid and a new α-keto acid. The reaction does not involve the release of ammonia and ensures the interconversion of amino acids in intermediary metabolism.
The coenzyme for all aminotransferases is pyridoxal phosphate (PLP), a derivative of vitamin B6.
Key transferases:
- AST (aspartate aminotransferase): aspartate + α-ketoglutarate ⇌ oxaloacetate + glutamate.
- ALT (alanine aminotransferase): alanine + α-ketoglutarate ⇌ pyruvate + glutamate.
Glutamate acts as a universal "collector" of amino groups, as it is the one that subsequently undergoes oxidative deamination.
Diagnostic significance of AST and ALT. De Ritis ratio
AST and ALT are organ-specific enzymes. ALT is predominantly localized in the cytosol of hepatocytes, whereas AST is found in hepatocytes as well as cardiomyocytes (both cytosolic and mitochondrial fractions). Upon cell damage, the enzymes leak into the blood, which is utilized in enzymodiagnostics.
- Acute viral hepatitis: ALT increases 6–8 fold or more, while AST increases moderately.
- Myocardial infarction: AST increases 8–10 fold, while ALT increases 1.5–2 fold.
De Ritis ratio = AST / ALT. The normal value is approximately 1.33.
- In hepatitis, the ratio drops to ≈ 0.6.
- In myocardial infarction, it is significantly greater than 1.
- In liver cirrhosis, it is around 1.
Amino acid deamination
Deamination is the removal of the α-amino group from an amino acid with the release of free ammonia (NH3) and the formation of the corresponding α-keto acid. Unlike transamination, the total number of amino acids decreases in the process—this is the initial stage of their catabolism.
The resulting α-keto acids (nitrogen-free residues) can enter:
- oxidation reactions in the Krebs cycle to produce energy;
- transamination for the resynthesis of amino acids;
- gluconeogenesis or ketogenesis.
Types of deamination:
- Direct—oxidative (characteristic of glutamate via glutamate dehydrogenase) and non-oxidative (for serine, threonine).
- Indirect (transdeamination)—the main pathway in humans: an amino acid transfers its amino group to α-ketoglutarate to form glutamate, which then undergoes oxidative deamination.
Ammonia is toxic, especially to the central nervous system, and therefore must be detoxified (primarily via the ornithine urea cycle).
Key points
- Pepsin is activated by HCl in the stomach; pancreatic proteases are secreted as zymogens.
- Enteropeptidase triggers the activation of trypsinogen; trypsin is the key activator of the entire proteolytic cascade.
- Premature activation of trypsinogen causes acute pancreatitis; therapy involves trypsin inhibitors (Contrical, Gordox).
- Transamination is a reversible reaction involving pyridoxal phosphate (vitamin B6), without the release of ammonia.
- AST and ALT are diagnostic markers of liver and myocardial injury.
- De Ritis ratio (AST/ALT): < 1 in hepatitis, > 1 in myocardial infarction.
- Deamination is a catabolic reaction resulting in the release of toxic NH3 and the formation of α-keto acids.
- The primary pathway in humans is indirect deamination via glutamate.