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Protein is derived from ________.
diet (50%), digestive secretions (25%, enzyme degraded by intestinal bacteria), and sloughed epithelial cells (25%, epithelial turnover)
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Protein digestion begins in ______ through the action of ________.
The ________ delivered to ______ are further degraded by ________ and ________.
Specific carriers transport _____ and ________ across _______. _______ further degrade _______ to _______, which are extruded from the cell into the blood by a variety of _________.
- polypeptides
- the small intestine
- pancreatic proteases
- brush border enzymes
- amino acids
- small peptides of 2-4 amino acids
- the brush border
- Cytosolic peptidases
- the small peptides
- amino acids
- basolateral transporters
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Because of _________, protein and amino acid deficiencies seldom result in malnutrition.
multiple transport pathways
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Compare lumenal, mucosal and cytosolic protein digestion. Describe the function of trypsin inhibitor. Discuss the importance of enterokinase and trypsin in protein digestion.
- lumenal: products: oligopeptide 70%; di/tri-peptides 30%, simple AAs
- mucosal: jejunum, 4-8 AAs oligopeptides -> di/tri-peptides
- cytosolic: mainly digest di-/tri-peptides into single AA; 90-99%
trpsin inhibtor prevents premature conversion of trpsinogen into trpsin in acinar cells; protective.
- enterokinase convert trpsinogen into trypsin inside duodenum and jejunum
- Trypsin autocatalyse more trypsinogen into trypsin, and convert other proenzymes into their active forms.
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Identify the primary intestinal sites for amino acid and small peptide absorption. Describe and compare the brush border mechanisms responsible for absorption of amino acids and small peptides.
- AA-> ileum
- small peptide-> jejunum
- small peptide:
- pepT-1 PAT
- H-gradient
- L-AA
- 2-3 AAs
- AAs:
- 5-7 systems overlapping affinities
- L-AA
- mainly Na-dependent, can be Na-independent too
- may have facilitated diffusion and channels
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Discuss the role of cytosolic peptidases and the pathways for transport of amino acids across the basolateral membrane.
cytosolic endo- or exo- peptidases convert 2-3AA peptide to simple AAs
- mainly Na-dependent
- bidirectional
- can be used during starvation to get AAs from blood
- minority Na-indepent
- net absorption of AA into blood
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Discuss the causes and primary symptoms of Hartnup’s Disease and the effect of disorders of amino acid transport on nutritional state.
lack transporter for neutral AA (phe, leu)
- non-lifethreatening
- neurodisorder: ataxia, psychiatric abnormality, photo sensitivity
- non-fatal
- multiple carrier/pathway exist
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Protein Function
tissue repair, maintenance and growth
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Protein Digestion Types
- - luminal
- - mechanical (motility)
- - chemical (enzymes)
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Digestive Sites
- Mouth
- 1) luminal; 2) mechanical (chewing)
- Stomach, Intestine - Two Types
- 1) mechanical (motility) - luminal
- 2) chemical - HCl less important
- - proteases – pancreatic acinar cells - essential
- - protease subtypes - activated in gut
- - exopeptidases - cleave single amino acid from C- terminal peptide
- - endopeptidases - cleave interior peptide bonds adjacent to AAs
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endopeptidases
- - cleave interior peptide bonds adjacent to amino acids
- - enter lumen in inactive form then converted to active form
- - produce small peptides - 2-6 amino acids
- - do not release individual acids
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Pepsin
- - Gastric Endopeptidase
- - secreted as proenzyme, pepsinogen by chief cells
- - activated by H+
- - pH optimum 1-3
- - activity terminated in small intestine
- - limited specificity - reduces about 15% into small peptides and amino acids (digesting collagen in meat)
- - HCl - lesser importance in direct gastric digestion
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Digestion in Small Intestine
- sites
- types in lumen
- proteases source and types
- Lumenal, Brush Border, Cytosolic
- - mechanical and chemical
- - 50% of total digestion
- - Acinar cell pancreatic proteases
- - endopeptidases
- - exopeptidases
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When ______ are secreted into the duodenal lumen, enterokinase, a _____ released from the _______ by ______, converts ______ to ______, which is ______, i.e. activates its own conversion from _______, as well as ________.
- inactive proteases
- hydrolase
- brush border
- bile salts
- trypsinogen
- trypsin
- autocatylic
- trypsinogen
- convert other proenzymes
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Trypsin
- - Pancreatic Endopeptidases
- - secreted as trypsinogen (proenzyme)
- - activated by enterokinase (enteropeptidase)
- - hydrolase from brush border, released by bile salts
- - highly concentrated @ duodenal & jejunal mucosa
- - 41% carbohydrate, not readily degradable by proteolytic enzyme
- enterokinase
- Trypsinogen ---------------------> trypsin
- - autocatalytic
- - converts other proteases
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Chymotrypsin and Elastase
- - Pancreatic Endopeptidases
- - secreted as proenzymes
- - activated by trypsin
- - cleve proteins at neutral amino acids
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Pancreatic Exopeptidases
- - remove amino acid from C-terminal
- - secreted as proenzymes
- - activated by trypsin
- Trypsin
- Procarboxypeptidase (A/B) --------------> carboxypeptidase (A/B)
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Final Protease (lumenal) Digestion Products
- - oligopeptides (70%; >= 4 AAs)
- - di- or tri-peptides (30%)
- - simple amino acids
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As digestion progresses, the pancreatic enzymes ________
Trypsin _________
- get very rapidly inactivated
- digests itself, shuts down proteolysis, to prevent mucosal damage
-
Brush Border Digestion
- - Oligopeptides
- - enzyme preference - 4-8 amino acids
- - jejunum – highest activity
- - Final Products
- - primarily di- and tri- peptides
- - not too much osmotic gradient
- - small enough for mucosal transport
- - single amino acids
- - limited tetrapeptides
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Apical Small Peptides Absorption
- where
- transporter: energy, specificity
- advantage of the system
- primarily jejunum
- PepT-1 PAT (protein-dependent AA transporter) - primary
- - energy - H gradient
- - L-AAs - broad specificity (none for D-AAs)
- - highest affinity - 2-3 amino acids
- - tetrapeptides low affinity
- kinetic advantage
- - transport is "faster" than single AA
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Apical Amino Acids Absorption
- where
- what
- specificify
- dependence
- mechanism
- - ileum - major site
- - 5-7 systems with overlapping affinities - difficult to separate
- - L - amino acids - highest affinity
- - Na - dependent - majority
- - Na - independent (minority)
- - facilitated diffusion and channels postulated, in addition to active Na-cotransport
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Cytosolic Digestion of small peptides
- who
- specificity
- outcome
- special outcome and consequences
Endo or exo peptidases
di and tri linkages
90-99% amino acids
- few resistant peptides pass to circulation
- - produce anaphylaxis or hypersensitive responses
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Small intestine - Basolateral Transport - Amino Acids
- specificity
- dependence
broad specificity - at least 5
- Na-dependent
- - majority
- - bidirectional transport
- - important during starvation
- - can extract AAs from blood for cell maintenance
- Na-independent - minority
- - net secretion - absorption into blood
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Protein Deficiencies
- malnutrition - infrequent
- - multiple carriers and peptide absorption
- - passive - hydrophilic absorption
- - hydrophilic
child deficiencies -> jaw and tooth malformations
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Pancreatitis
autodigestion of pancreas
variable causes
- acute cases
- - biliary stones, alcohol
- - activates cascades of other proteases
- congenital
- - failure of trypsin inhibitor
- - trypsin not inactivated
- - Pancreatic acinar cells store proteases in inactive form in zymogen granules
- - cytosol contains trypsin inhibitor that discourages premature protease activation
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Hartnup’s Disease
- hereditary absence of neutral amino acid transporter in intestine and kidney
- - (B or NBB transporters) - transport phenylalanine, leucine
- - non-life-threatening
- - neurological disorders (ataxia), photosensitivity, psychiatric abnormalities
- PepT-1 and basolateral transporters – normal
- - neutral amino acids absorbed in small peptides
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Cystinuria
- Absence of transporter for basic amino acids (cysteine) in intestine and kidney
- - cystine in urine
- - causes kidney stones
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