Biochemistry of Digestion and Absorption

Gastrointestinal System

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Three Stages of Catabolism

Major events involved in food digestion and absorption

1. Mechanical homogenization & mixing of food with GIT fluids

2. Secretion of enzymes for hydrolysis of food molecules

3. Secretion of electrolytes, acid or base to provide an optimum environment for enzymatic digestion

4. Secretion of bile acids/salts for digestion and absorption of lipids

5. Enzymatic hydrolysis of large food molecules

6. Transport of hydrolyzed food molecules across the intestinal epithelial cell into blood

Major Constituents of SalivaMucins • a mixture of glycoproteins (60-85%

oligosaccharide)

• forms viscous lubricating solutions

α -Amylase • Catalyzes the hydrolysis of only α(1→4)

glucosidic bonds of starch and glycogen

• Has minimal role in digestion

Lingual Lipase:• Initiates hydrolysis of dietary fat in the

stomach and facilitates the duodenal-jejunal hydrolysis of TGs.

Major Constituents of Gastric SecretionsConstitu-ents

Source Major functions

HCl (acid) Parietal cells

Kills microbes, dissolves food particles, activates pepsinogen into pepsin and provides optimum pH for pepsin

Pepsinogens (Pepsin)

Chief cells Begins initial hydrolysis of proteins (optimum pH 2-4)

Rennin (only in infants)

Stomach Causes milk clotting & promote its digestion by preventing rapid passage from the stomach.

Gastric lipase

Chief & mucous cells

An acid stable lipase that digest short chain fatty acid

Gastrin G cells Stimulates acid secretion by stomachMucus Mucous cells Protects stomach, moistens food

Major constituents of pancreatic and bile secretions

Constituents Source Major functionsNaHCO3

- Hepatocyte; Centroacinar & duct cells (Pancreas)

Neutralizes acidic chyme in the duodenum & maintains optimum alkaline pH for the digestive enzymes

Enzymes Acinar cells (Pancreas)

Include amylase, peptidases and lipases. Digest partially degraded starch, proteins and lipids

Bile salts Hepatocytes Detergent mols. Stimulates intestinal lipase and emulsify lipids for their digestion and absorption

Major constituents of secretion from small intestine

Constituents Source Major functions

Secretin S cells Stimulates NaHCO3- secretion from

exocrine pancreas

Cholecystokinin (CCK)

I cells Stimulates gallbladder contraction to release bile and pancreas to secrete NaHCO3 & enzymes, increases intestinal motility

Gastric Inhibitory Peptide (GIP)

K cells Stimulates insulin secretion from endocrine pancreas & inhibit gastric secretion and motility

Possible biochemical causes of digestive disorders

Digestive disorders can arise as a result of:

(1) Enzyme deficiency, eg, lactase and sucrase;

(2) Malabsorption, e.g, of glucose and galactose as a result of defects in the Na+-glucose cotransporter (SGLT 1);

(3) Absorption of unhydrolyzed polypeptides leading to immune responses, e.g, as in Celiac disease; and

(4) Precipitation of cholesterol from bile as gallstones.

Digestion and Absorption of Carbohydrates

Dietary Carbohydrates• Constitute about 40-50% of the calories of average diet • Can be of two types:

a. Non-digestible carbohydrates e.g. Celluloseb. Digestible carbohydrates e.g. sugar, starch, glycogen

Disaccharides Polysaccharides

Digestion of Carbohydrate

Starchα -1, 4

α -1, 4

α -1, 4α -1, 4

Digestion of Carbohydrate

Clinical Correlation

• Serum amylase and lipase are elevated in cases of pancreatitis

• Acarbose, an α-glucosidase inhibitor, treatment of DM.

Digestion of cellulose

• Cellulose contains β(1-4) bonds between glucose molecules.

• In humans, there is no β (1-4) glucosidase that can digest such bonds. So cellulose passes as such in stool.

• Cellulose helps water retention during the passage of food along the intestine producing larger and softer feces preventing constipation.

Glucose TransportersTypes Tissue locations Functions

A. Facilitative bidirectional transportersGLUT 1 Brain, kidney, colon, placenta,

RBCsGlucose uptake

GLUT2 Liver, pancreas, small intestine, kidney

Rapid uptake or release of glucose

GLUT3 Brain, kidney, placenta Glucose uptake

GLUT4 Heart & skeletal muscle, adipose tissue

Insulin-stimulated glucose uptake

GLUT5 Small intestine Absorption of glucose, fructose and galactose

B. Na-dependent unidirectional transporter

SGLT-1 Small intestine and kidney Active uptake of glucose against concentration gradient

• Glucose & galactose are absorbed by the same SGLT-1 from the intestinal lumen

• Other monosaccharides are absorbed by carrier-mediated diffusion via GLUT 5

• Monosaccharides are then released into the blood through GLUT2

• Both GLUT2 and GLUT5 are insulin insensitive

Absorption of digested carbohydrates

Lactose Intolerance

• Prevalence: Most common among adults of African or Asian descent

• Cause: A genetic defect resulting decreased amount of lactase

• Symptoms: Bloating, diarrhea and dehydration

• Diagnosis: Oral tolerance test and measurement of H2 gas in the breath

• Treatment: less intake of milk, use of lactase-treated products; or intake of lactase pills prior to eating.

Digestion and Absorption of Proteins

Introduction• Most of the dietary N2 is consumed in the form of

protein

• An average diet may contain 70–100 g of proteins

• Proteins are generally too large to be absorbed

• They must, therefore, be hydrolyzed to yield their constituent amino acids, which can be absorbed.

• Proteases are produced by three different organs of GIT: stomach, pancreas, and small intestine

Proteases• Enzymes that hydrolyses peptide bonds of proteins

• Many are synthesized as larger, inactive forms known as zymogens

• Are of two main types:

• Endopeptidases: cleave peptide bonds within protein chains

• Exopeptidases: cleave one amino acid progressively from the C-or N-terminal end of the peptide

Proteases

Examples of Endopeptidases

Examples of Exopeptidases

Can be of two subtypes:

• Carboxypeptidases: release amino acids from the free carboxyl terminal e.g.

• Aminopeptidases: cleave one amino acid at a time from the N terminus of peptides

Why Zymogens?

• Proteases and phospholipases (but not lipases and glycosidases) are dangerous digestive enzymes.

• Must be kept chained and muzzled until they reach the GIT lumen

• Otherwise they attack proteins and membrane lipids in the cells of their birth and cause auto-digestion.

• This is always prevented by synthesizing them in inactive form (zymogens)

Activation of the gastric and pancreatic zymogens

Digestion of Proteins

• Mouth: No protein digestion

• Stomach: Begins in the stomach & completes in the intestine

• Gastric HCl denatures proteins & pepsin hydrolyses them into peptide fragments and free AAs.

• Pepsin hydrolysis contributes about 10-15% of dietary proteins but not essential for survival

Digestion of Proteins • Small intestine: Further digestion

in intestine is carried out by pancreatic proteases

• HCO3- maintains opt. alkaline pH

for proteases

• Amino-, di- & tri-peptidase secreted from/present inside the epithelial cells complete the last step of digestion

• Free AAs are then absorbed and transported by portal circulation

Clinical CorrelationNontropical sprue (adult celiac disease) • A general malabsorptive disorder due to consumption of gluten

containing foods (wheat, rye and barley)

• Cause: Contain toxic protein called gliadin which produce antibodies to endomysium of smooth muscle and causes damage to the small intestine

• High-risk populations: Patients with Down's syndrome, type 1 DM, lupus and rheumatoid arthritis

• Diagnosis: Intestinal biopsy and serological testing for antigliadin and antiendomysial antibodies

• Treatment: Life-long complete abstinence from gluten- containing food

Clinical Correlation

Achlorhydria

• lack of ability to produce HCl (due to autoimmune destruction of gastric parietal cells)

• Deficiencies in protein digestion and absorption

Peptic Ulcer

• Bicarbonate is released from the pancreas in response to the hormone secretin

• Failure to fully neutralize the acidic gastric contents results in peptic ulcers in the duodenum.

Lumen of small intestine

Amino acids

Amino acids

Amino acids

Interstitial fluid Blood

Na+/aasymport

amino acid carriers

(facil. diffusion)

mucosalcell

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Na+,K+

ATPasepump

Na+ H+

Na+

Na+

K+

K+

Na+Small

peptidesH+

Small peptides

Absorption of Amino acids and Small peptides

H+/peptidesymport

AminopeptidaseDi- and tripeptidases

• Absorbed by two different mechanisms

a. Na+ & H+ dependent symport systems for AAs & small peptides

b. Facilitated diffusion for the release of absorbed AAs into the blood

Disorders of Protein digestion & absorption

Hartnup disease (Neutral amino aciduria)

Cystinuria

Digestion and absorption of Lipids

Lipid Digestion and Absorption• A heterogeneous group of hydrophobic org. molecules

• Provides maximum amount of energy for the body

• Average adult daily intake is about 30-50g

• Dieatary lipids consist of mainly TGs (>90%) and other lipids (<10%) e.g. cholesterol, cholesteryl esters, phospholipids, and free FAs.

• Normally, 95% of ingested lipids are digested and absorbed

• Digestion (hydrolysis) is only partial and requires the presence of bile acids/salts

Enzymes involved in lipid digestionLipase: Hydrolyses ester bonds of TG

Triacylglycerol + 2H2O 2-Monoacylaglycerol + 2 FA

Lingual : -Contributes very less to fat digestion & acid stable

-Active in small intestine if no HCO3- is secreted

Gastric : -Hydrolyses TGs with short & medium-chain FAs

-May also hydrolyse about 10-30% TGs with long chain FAs

Pancreatic -Responsible for the majority of digestive action

-Uses a cofactor colipase-bound both to lipase & micelle surface

-Colipase reduces the surface tension at the lipid-aqueous interface

Enzymes involved in lipid digestionPhospholipase A2Phosphatidylcholine + H2O 2-lysophosphatidylcholine + FA

• Secreted by pancreas in active proenzyme (zymogen)• Activated by trypsin• Partially hydrolyzes both dietary phospholipids and

hepatobiliary phosphatidylcholine• Specific for FAs in 2-position of phospholipids

Cholesteryl esteraseCholesteryl ester + H2O Cholesterol + FA

• Secreted by pancreas• Hydrolyses cholesteryl esters with long chain FAs

Mixed Micelle• Bile salts form micelles

• Mixed micelles formed in the gut contains dietary lipids and bile salts

• Bile salts form the edge whereas lipids exist in a bilayer on the inside of the micelle

• Provide a large surface area for the action of pancreatic lipase

• Also facilitates the absorption of digested lipid by gut enterocytes

Digestion of Lipids

Clinical CorrelationOrlistat:– an anti-obesity drug that inhibits pancreatic & gastric lipase

– blocks about 30% of dietary fat from digestion and absorption

– leads to reduction in body weight in some patients

Olestra:– an artificial fat composed of a sucrose polyester & fatty acids

– not degraded by gastric or pancreatic lipases

– passes through undigested and unabsorbed

– excess use may interfere with absorption of fat-soluble vitamins

Absorption of lipids

• Products of lipid digestion are solubilized and converted into small mixed micelles by bile salts

• These micelles diffuse from the intestinal lumen towards cytosol of the mucosal cells for their absorption.

Formation & secretion of chylomicrons

Lymph

Disorder of Lipid Digestion and Absorption

Steatorrhea• Results due to Impaired functioning of any of the

components of lipid digestion and absorption

• Leads to excretion of fat in foul-smelling, bulky stools, and poor absorption of fat-soluble vitamins.

• Can occur due to three major reasons:

– Impaired hydrolysis of TG

– Insufficent secretion of bile

– Impaired absorption by the intestinal mucosa

Abnormalities of Lipid Digestion due to Impaired Lipolysis

Type of Defect Biochemical Disturbances Disease States (e.g.)

Rapid gastric emptying

Reduction in the efficiency of lipid interaction with bile & pancreatic secretions

Gastrectomy, as in treatment of ulcer or neoplasm of stomach

Acidic duodenal pH

Inactivation of pancreatic lipase & decreased ionization of bile acids

Zollinger-Ellison syndrome

Decreased CCK released

Deficiency of bile & pancreatic secretions

Disorders associated with mucosal destruction, regional enteritis, Hartnup disease

Abnormalities of Lipid Digestion due to Impaired Lipolysis

Type of Defect Biochemical Disturbances Disease States (e.g)

Congenital lipase or colipase deficiency

Defective lipolysis

Pancreatic insufficency

Defective lipolysis Chronic pancreatitis, Pancreatic duct obstruction (e.g. cystic fibrosis)

Absent or decreased bile salts

Decreased lipolysis due to impiared micelle formation

Severe parenchymal liver diseases

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