Protein Digestion and Metabolism

Learning Objectives

• Understanding the digestion and absorption of protein, amino acid synthesis and degradation is key
• It's important to apply the role of transaminases in amino acid metabolism
• Analyzing and evaluating the diseases associated with protein metabolism should be done

Overview

• Proteins are digested into monomers of amino acids in stage 1
• Stage 2 involves monomers becoming a form that can be completely oxidized, usually acetyl-CoA
• Complete oxidation of acetyl-CoA and the production of ATP occur during stage 3
• The term "protein" comes from the Greek word "proteious," meaning primary, highlighting their significance as major components of living organisms
• Proteins are high molecular weight substances, containing carbon, hydrogen, oxygen, nitrogen, and sometimes sulfur and phosphorus
• Proteins are crucial for cell membranes and cytoplasm
• Specific proteins are found in muscles and blood plasma
• Proteins facilitate numerous chemical reactions in the body
• Proteins play roles as hormones, antibodies, transporters, and more, reflecting their diverse biological functions
• Protein-rich foods are essential for life
• Proteins are vital for body structure and provide energy similar to carbohydrates

Digestion and Absorption of Proteins

• Proteins are large polypeptide molecules that are broken down into amino acids through enzymatic hydrolysis during digestion
• The gut receives 70-100g of dietary protein and 35-200g of endogenous protein daily
• Only 1-2g of nitrogen, equivalent to 6-12g of protein, is lost in feces, indicating efficient digestion and absorption
• Protein digestion is categorized based on the sources of peptidases involved
• The average protein intake for healthy young adults is 80 to 120 g/d, with 6 g of protein yielding about 1 g of nitrogen and providing 4 kcal of energy
• Gastric digestion begins when protein enters the stomach, triggering the gastric mucosa to release the hormone gastrin
• This stimulates parietal cells to secrete HCl and chief cells to produce pepsinogen
• The HCl produced lowers stomach pH to between 1.5 and 2.5, serving as an antiseptic that kills bacteria and denatures proteins, enhancing their susceptibility to proteolytic enzymes
• Proteases, specifically endopeptidases, break internal bonds in peptides, releasing large fragments
• Pepsinogen converts to active pepsin in the stomach after removing 44 amino acids
• Active pepsin cleaves proteins at the amino terminus of aromatic amino acids (Phe, Tyr, Trp), resulting in large peptide fragments and some free amino acids
• Pancreatic digestion begins when acidic stomach contents enter the small intestine
• A low pH triggers the release of the hormone Secretin, which prompts the pancreas to secrete bicarbonate (HCO3) to neutralize gastric HCL and adjust the pH to 7.0
• The presence of large peptide fragments and free amino acids in the duodenum stimulates the release of cholecystokinin (CCK)
• Three pro-enzymes trypsinogen, chymotrypsinogen, and procarboxypeptidase are produced by exocrine cells as inactive precursors to protect against proteolytic damage
• In the small intestine, enteropeptidase activates trypsinogen to trypsin by removing a hexapeptide.
• Trypsin then activates more trypsinogen and other pro-enzymes, releasing chymotrypsin, elastase, and carboxypeptidases
• Through the action of proteolytic enzymes, ingested proteins are broken down into free amino acids that can be absorbed through the small intestine's epithelial lining
• Intestinal digestion relies on small intestinal enzymes since pancreatic juice lacks significant aminopeptidase activity
• Epithelial cell surfaces contain endopeptidases, dipeptidases, and aminopeptidases that break down peptides into free amino acids and di- and tripeptides
• Amino acids are absorbed by epithelial cells and converted by peptidases, then transported to the bloodstream and primarily delivered to the liver, completing 99% of protein absorption
• Glucose uptake resembles amino acid transport, involving Na+ dependent symporters and ATP linked Na+ pumping, classifying it as indirect active transport
• A similar H+ dependent symporter exists for di- and tripeptides
• Na+ independent transporters also help transport amino acids to the hepatic portal system, with at least six specific symporter systems identified for L-amino acid uptake from the intestinal lumen
• Neutral amino acid symporters exist for short or polar side chains like Ser, Thr, Ala, and aromatic/hydrophobic side chains like Phe, Tyr
• An amino acid symporter exists for Pro and OH-Pro
• A basic amino acid symporter exists for Lys, Arg, Cys
• An acidic amino acid symporter exists for Asp, Glu
• B amino acid symporter: B-Ala, Tau
• Hartnup disease is caused by defects in renal tubule transporter systems, impacting neutral amino acid absorption
• It leads to aminoaciduria due to the kidneys' inability to reabsorb amino acids and causes deficiencies in essential amino acids and nicotinamide
• Symptoms include pellagra-like features from tryptophan deficiency
• Di- or tripeptide transport systems remain unaffected, allowing absorption of protein digestion products

Amino Acid Synthesis

• Amino acid synthesis is crucial for the human body
• Amino acids serve as building blocks for proteins and other essential biological molecules like nucleic acids, hormones, neurotransmitters, antioxidants, and signaling molecules
• Amino acids are sourced from proteins and synthesized de novo for nitrogenous compound and protein production
• Their carbon skeletons serve as fuel based on energy needs, while toxic nitrogen waste is primarily excreted as urea
• Essential amino acids are typically diet-derived, while non-essential amino acids can be produced from other sources
• Non-essential amino acids are synthesized from precursors derived from carbohydrate metabolism
• The 20 amino acids in humans mainly originate from carbohydrate metabolism (glycolysis and citric acid cycle)
• Essential amino acids must be obtained from the diet, they are marked with asterisks
• Histidine is partly derived from the nucleic acid precursor phosphoribosyl pyrophosphate and glutamate
• Certain medical conditions are linked to amino acid synthesis

Amino Acid Degradation

• Protein and amino acid degradation is vital for energy when carbohydrates and lipids are scarce
• It also aids in nitrogen regulation by converting excess nitrogen into urea for excretion
• Each amino acid undergoes specific enzymatic reactions that connect to carbohydrate and lipid metabolism
• Enzyme deficiencies in these pathways can lead to congenital diseases requiring specific dietary management
• Several diseases related to enzyme deficiencies in amino acid metabolism can lead to developmental issues
• Neurological problems such as unique behaviors (like repetitive self-hugging)
• This can cause musculoskeletal disorders, abnormal organ functions, and distinctive odors (e.g., "maple syrup," "mousy")

Clinical Significance

• Amino acid deficiencies can lead to conditions like kwashiorkor and marasmus due to inadequate protein intake, particularly in West Africa
• Short bowel syndrome patients face significant nutritional issues
• Disorders like scurvy (vitamin C deficiency) impair collagen formation, causing bleeding gums and poor healing
• Menkes syndrome arises from copper deficiency, affecting collagen strength
• Genetic disorders such as osteogenesis imperfecta and Ehlers-Danlos syndrome involve collagen biosynthesis defects, resulting in fragile bones and connective tissue problems
• After injury, glucocorticoids increase protein breakdown, leading to urinary nitrogen excretion over 30 g/d, equating to a daily loss of 1.5% lean body mass
• Without nutrition for 10 days, an injured person could lose 15% of lean body mass
• Amino acids aren't a long-term fuel source, and excessive protein loss (25% to 30% of lean body weight) is life-threatening
• Protein degradation post-injury supplies substrates for gluconeogenesis and acute phase protein synthesis
• Skeletal muscles are quickly depleted after injury, while visceral tissues like the liver and kidney are preserved
• Increased urea excretion after injury is linked to the loss of intracellular elements (sulfur, phosphorus, potassium, magnesium, creatinine), while the rapid use of potassium and magnesium during recovery suggests tissue healing
• Protein synthesis and degradation changes depend on injury severity and duration
• Elective surgeries and minor injuries lead to lower protein synthesis and moderate breakdown, while severe trauma, burns, and sepsis cause increased catabolism.
• Urinary nitrogen rises and negative nitrogen balance can be detected early post-injury, peaking by day 7
• Protein degradation may last 3 to 7 weeks
• Prior physical status and age influence proteolysis levels after injury or sepsis
• The ubiquitin-proteasome system in muscle cells is a key pathway for protein degradation during acute injury, affected by tissue hypoxia, acidosis, insulin resistance, and high glucocorticoid levels

Summary

• The processes reveal how our bodies use protein for health
• Transaminases are key in transferring amino groups for non-essential amino acid synthesis
• Disruptions can cause metabolic disorders, highlighting the need for balanced protein intake
• Further research can help develop therapies to manage or prevent these disorders