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Digestive enzymes

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Mechanical homogenization of food, mixing with fluids secreted by the glands of GIT ... Pancreas is the major organ that synthesizes the digestive enzymes ... – PowerPoint PPT presentation

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Title: Digestive enzymes


1
Digestive enzymes
  • mirka.rovenska_at_lfmotol.cuni.cz

2
Various organs in digestion and absorption
  • Pancreas is the major organ that synthesizes the
    digestive enzymes

3
Small intestine is a principal site of digestion
and absorption
and there are 3 compartments where digestion and
absorption occur
  • Pancreatic enzymes together with bile are poured
    into the lumen of the descending part of the
    duodenum
  • Digestion of oligomers of AA and saccharides is
    accomplished by the enzymes in the luminal plasma
    membranes of enterocytes these enzymes usually
    glycoproteins
  • Hydrolysis of di- and tripeptides occurs in the
    cytoplasm of enterocytes

4
Zymogens
  • Digestive enzymes are usually synthesized as
    larger inactive precursors zymogens
  • Otherwise they would digest the tissues that
    synthesize them
  • acute pancreatitis premature activation of
    digestive enzymes produced by pancreas ?
    auto-digestion of pancreas activated
    phospholipase A2 converts lecithin to
    lysolecithin that can damage cell membranes

5
Synthesis of zymogens
  • Proteins destined for secretion are synthesized
    on polysomes of the RER
  • Their N-terminus contains a signal sequence ?
    release of the protein into ER then, the signal
    sequence may be clipped off
  • Transport to the Golgi complex
  • The proteins are stored in vesicles after
    stimulus, granules move to the luminal plasma
    membrane (PM) and fuse with PM exocytosis

6
Zymogens are activated by proteolysis
  • Proenzymes (zymogens) are activated by
    proteolytic cleavage in the lumen of the GIT
  • pepsinogen
  • trypsinogen
  • chymotrypsinogen
  • proelastase
  • procarboxypeptidases
  • prophospholipases

7
Activation of pepsinogen
  • Pepsinogen is secreted from the stomach cells
  • Pepsinogen is activated by the proteolytic
    removal of 44 AA from its N-terminus either as
    an intramolecular reaction or by active pepsin
  • This reaction takes place at pH values below 5

8
Activation of pancreatic zymogens in the lumen
of the small intestine
9
Strategies that prevent premature zymogen
activation
  • At pHgt2, the peptide (44 AA) clipped of
    pepsinogen remains bound to pepsin, masking its
    active site it is released by a drop of pH below
    2 or by further degradation by pepsin
  • Pancreatic secretory trypsin inhibitor (PSTI), a
    small polypeptide, blocks any trypsin that is
    erroneously activated within the pancreas

10
Regulation of secretion
  • Through secretagogues that interact with the
    receptors on the surface of the exocrine cells ?
    signal cascade leading to fusion of granules with
    PM
  • Cholecystokinin peptide secreted by cells of
    small int. after stimulation by AA and peptides
    from gastric proteolysis, by FA, and by acid pH
  • Secretin peptide secreted by cells of small
    int. stimulated by luminal pH lt 5

Organ Secretion Secretagogue
Salivary gland NaCl, amylase acetylcholine
Stomach HCl, pepsinogen acetylcholine, histamine, gastrin (peptide)
Pancreas NaCl, enzymes acetylcholine, cholecystokinin
Pancreas NaHCO3, NaCl secretin
11
DIGESTION OF PROTEINS
  • By peptidases (proteases)
  • endopeptidases attack internal bonds
  • pepsin
  • trypsin
  • chymotrypsin
  • elastase
  • exopeptidases cleave off 1 AA at a time from
    the
  • C-terminus carboxypeptidases
  • N-terminus aminopeptidases

12
Classes of peptidases
Type Active site pH optimum
Serine proteases Ser, His, Asp 7-9
Cysteine proteases Cys, His 3-6
Aspartate proteases 2 x Asp 2-5
Metalloproteases Zn2 (coordinated to AA) 7-9
13
Peptidases hydrolyze the peptide bond
and differ in substrate specificity
14
Pepsins
  • Acid in the stomach serves to kill off
    microorganisms and to denature proteins
    (denaturation makes proteins more susceptible to
    proteolysis)
  • Pepsins are acid stable and pH optimum is about
    2!!!
  • Major products of pepsin action larger peptide
    fragments and some free AA this mix peptone
  • Importance lies mainly in generation of peptides
    and AAs that stimulate cholecystokinin release in
    the duodenum

15
Pancreatic enzymes
  • trypsin
  • chymotrypsin
  • elastase
  • carboxypeptidases
  • Active at neutral pH ? depend on neutralization
    of gastric HCl by pancreatic NaHCO3
  • The combined action of pancreatic peptidases
    results in the formation of free AA and small
    peptides (2-8 AA)

16
Intestinal peptidases
  • Luminal surface of intestinal epithelial cells
    contains endopeptidases, aminopeptidases, and
    dipeptidases that cleave oligopeptides released
    by pancreatic peptidases
  • Products AA, di- and tripeptides ? absorbed by
    enterocytes
  • Di- and tripeptides are hydrolyzed by intestinal
    cytoplasmic peptidases
  • AA are absorbed into the portal blood

17
DIGESTION OF SACCHARIDES
  • 1) Polysaccharides (starch, glycogen) are
    attacked by ?-amylase, which is present in saliva
    and pancreatic juice (more important)
  • ?-amylase attacks the internal ?-1,4-glucosidic
    bonds ? products maltose, maltotriose, ?-limit
    dextrins

18
  • 2) Hydrolysis of oligosaccharides is carried out
    by surface enzymes of the intestinal epithelial
    cells disaccharidases and oligosaccharidases
  • These enzymes often exoglycosidases

19
Saccharide absorption
  • End products monosaccharides, mainly D-glucose,
    D-galactose, D-fructose
  • These are transported by a carrier-mediated
    process into enterocytes and then into the blood
    of the portal venous system

20
Not everything can be digested
  • Many plant polymers, including celluloses,
    hemicelluloses, inulin, pectin, are resistant to
    human digestive enzymes
  • A small percentage of this dietary fibre is
    hydrolyzed and then anaerobically metabolized by
    the bacteria of the lower intestinal tract
  • This bacterial fermentation produces H2, CH4,
    CO2, H2S, acetate, propionate, butyrate, lactate

21
Lactase deficiency
  • Experienced as milk intolerance
  • Cause
  • a) genetic defect
  • b) decline of lactase activity with age
  • c) decline of activity due to an intestinal
    disease
  • Inability to absorb lactose ? accumulation and
    bacterial fermentation of lactose ? production of
    gas (distension of gut, flatulence) osmotically
    active solutes draw water into the intestinal
    lumen (diarrhea)

22
Lysozyme
  • Hydrolyzes ?-1,4-glycosidic bonds in the
    bacterial cell wall polysaccharide peptidoglycan
  • Kills only some types of bacteria

23
DIGESTION OF LIPIDS
  • Lipids sparingly or not at all soluble in
    aqueous solutions
  • Two problems have to be overcome
  • poor accessibility of the substrate to the enzyme
  • aggregation of products of hydrolysis to larger
    complexes that are hard to absorb

24
Steps in lipid digestion absorption
25
Lipid digestion is initiated in stomach
  • In the stomach, acid-stable lipase, secreted by
    stomach (gastric lipase) and by lingual glands
    (lingual lipase), converts TG mostly into FA and
    1,2-diacylglycerols (small amount of monoAG is
    also produced)
  • The products possess both polar and non-polar
    groups ? act as surfactants stabilize the
    water-lipid interface ? dispersion of the lipid
    phase into smaller droplets (emulsification) ?
    better availability of the substrate to the
    lipases.
  • These lipases have the unique ability to initiate
    the degradation of maternal milk fat globules

26
Pancreatic lipase
  • Cleaves acylglycerols mainly to FA and
    2-monoacylglycerols
  • Requires solubilization of the substrate
  • Also requires colipase (secreted by the pancreas)
    that anchors and activates the enzyme
  • Absorption of resulting FA and monoAG requires
    bile salts micelles

27
Digestion of phospholipids
  • By phospholipases, especially by phospholipase A2
    (requires bile acids for activity)
  • FA and lysophospholipids are absorbed from the
    bile acid micelles
  • In the intestinal mucosa, the absorbed
    lysophospholipids are reacylated with acyl-CoA

28
Hydrolysis of cholesterol esters
  • By pancreatic cholesterol esterase
  • The free cholesterol is transported in the bile
    acid micelles and absorbed through the brush
    border
  • Here, it is reacylated with acyl-CoA

29
Bile acid micelles solubilize lipids
  • Primary bile acids are synthesized by the liver
    and in peroxisomes, they are conjugated with
    glycine or taurine (H2N-CH2CH2SO3-)
  • A portion of the primary bile acids is subjected
    to the modifications by intestinal bacteria ?
    secondary bile acids
  • Primary and secondary bile acids are reabsorbed
    by the ileum into the portal blood, taken up by
    the liver, and then resecreted into the bile
    enterohepatic circulation

30
Bile acid has a hydrophobic surface and a
hydrophilic surface
  • The most abundant bile salt in humans
    glycocholate

31
Bile acid micelles
  • Hydrophobic region of the bile salt is oriented
    from the water molecules x hydrophilic region
    interacts with water
  • Mixed micelles contain (beside bile acids)
    phospholipids and cholesterol, or FA and
    acylglycerols FA and phospholipids form a
    bilayer in the interior, bile salts occupy the
    edge.

32
  • Released FA and monoacylglycerols are
    incorporated into bile acids micelles
  • Micelles move lipids from the intestinal lumen to
    the cell surface where absorption occurs
  • Micelles also serve as transport vehicles for
    vitamins A, K
  • Fat malabsorption can result from pancreatic
    failure or lack of bile acids ? bulk of
    unabsorbed lipids is excreted with the
    stoolsteatorrhea

33
Fat digestion and absorption
34
Most absorbed lipids are incorporated into
chylomicrons
  • Within the intestinal cell (after absorption)
  • FA of medium chain lenght (6-10C) pass into the
    portal blood without modification
  • long-chain FA (gt 12C) are bound to a fatty acid
    binding protein in the cytoplasm and transported
    to ER, where they are resynthesized to TG
  • TG form lipid globules to which phospholipids,
    cholesterol (esters), and apolipoproteins adsorb
    chylomicrons
  • chylomicrons migrate through the Golgi to the
    basolateral membrane, they are released, and pass
    into the lymphatics

35
DIGESTION OF NUCLEIC ACIDS
  • Pancreatic enzymes hydrolyze dietary nucleic
    acids
  • ribonucleases
  • deoxyribonucleases
  • Polynucleotidases of the small intestine complete
    the hydrolysis to nucleotides which are then
    hydrolyzed to nucleosides by phosphatases and
    nucleotidases
  • Nucleosides are used as such or undergo
    degradation by nucleosidases / nucleoside
    phosphorylases to free bases and
    pentose-1-phosphate

endo- as well as exonucleases
36
  • Purine nucleosides are
  • A) catabolized to uric acid
  • B) alternatively, purines are released and used
    for resynthesis of NA

37
  • Pyrimidine nucleosides are
  • A) catabolized to NH4, CO2, and
    ß-aminoisobutyrate or ß-alanine, respectively,
    that are partially converted to
    (methyl)malonyl-CoA
  • B) absorbed intact and utilized for the
    resynthesis of nucleic acids
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