Lecture 13 Protein-AA Digestion and absorption Flashcards
What are the 4 phases of AA digestion?
- mechanical digestion (not chemical) in the mouth
- gastric hydrolysis (chemical) in the stomach
- pancreatic proteases in the duodenum of SI resulting in smaller peptides
- Hydrolysis of peptide linkages at the brush border mainly in jejunum
Describe digestion of protein in the mouth
mechanical breakdown by the mouth and salivary glands assist
* chewing and crushing moistens protein-rich food and mix them with saliva to be swallowed
Describe digestion of protein in the stomach
start of chemical digestion via gastric juices containing hydrochloric acid (HCl) and pepsin
Role of HCl and pepsin in the stomach for protein digesiton
HCl: pH of 2-3 and denatures the tertiary and secondary protein structure to make make it linear then it activates the zymogen pepsinogen to pepsin
Pepsin: breaks the peptides bonds so linear protein becomes smaller peptides + free AA and inhibits pepsinogen synthesis
Why are many enzymes released for AA digestion in the zymogen form?
To prevent unwanted protein degradation, and to enable spatial and temporal regulation of proteolytic activity.
Describe protein digestion by the pancreas and the SI.
- polypeptide and AAs stimulate the release of cholecystokinin (CKK) which is secreted from the SI enteroendocrine cells of the duodenum
- CKK goes to the pancreatic aciner cells and stimulates the release of pancreatic juice which is secreted to the SI.
- pancreatic juice releases bicarbonate and zymogens in the lumen
- bicarbonate neutralizes the acidic environment to optimal pH of 6-7 for SI enzymatic activity
- The zymogen cascade can begin by becoming active enzymes and breaking whole proteins down to free AA, di-, tri-, oligo-peptides
Describe the zymogen cascade that occurs in the SI
Once pH is 6-7 the duodenual enterocytes release enteropeptidase which cleaves off a section of the zymogen trypsinogen (from pancreatic juice) to trypsin and this reaction activates a bunch of reactions to convert zymogens to active enzymes which have peptide bond specificity and break proteins down into small peptide and some free AA
* most activation of zymogens occurs cleaving of a section (but not always)
What are incretins?
Hormones that stimulates insulin secretion in response to meals.
* The two most important incretin hormones are called glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) which are secreted from the SI to communicate with pancreas, and are inactivated by the apical membrane bound enzyme DPP-4 which cleaves N terminal dipeptides from polypeptides containing proline and alanine.
What medication can be used in diabetes to increase glucose uptake?
DPP-4 inhibitor drugs (sitagliptin) which block the DPP-4 thus the incretins stay activated and continue to stimulate insulin release and inhibit glucagon release.
What further break down occurs after pancreatic enzymes?
brush border peptidases resulting in free AAs and small amount of di- and tri-peptides.
What are considered digestive juices?
- saliva
- gastric juice
- pancreatic enzymes
Where do endogenous proteins come from?
- digestive juices ~17 g
- desquamated intestinal cells sloughed off and absorbed by the body ~15 g
How much of protein do excrete through feces in a day?
~3-6 g/day
What are the different points of digestion in the SI?
- luminal digestion
- membrane digestion
- cytoplasmic digestion
What size of peptides can be transported into the membrane cells for cytoplasmic digestion?
- amino acid transport proteins for free AAs
- peptide transport protein for dipeptides and tripeptides
protein transport/ absorption process
- brush border peptidases break down large peptides into free AA and di-/tri-peptides
- brush border free AA transport systems
- Brush border peptide transport system (di-/ tri-)
- cytoplasmic peptidases break the di- and tri- into free AA.
- basolateral free AA transport systems
- basolateral peptide transport system (di-/ tri-)
How much of free AA, di- and tri-peptides are transported through the apical membrane versus the basolateral membrane?
- free AA: ~20% through the apical membrane and then ~ 90% through the basolateral membrane
- di- and tri-peptides: ~80% through the apical membrane and then ~10% through the basolateral membrane
How are the di- and tri- peptides transported through the membranes?
transporter are linked to osmolarity
1. H+/peptide cotransporter in the brush border membrane
2. Na+/H+ exchanger in the brush border membrane
3. peptide transport system(s) in the basolateral membrane (most di- and tri- are cleaved to free AA)
Classification of AA transporters on brush border membrane
essentially the transporter system is complicated and requires cotransport fo different ions depending on the charge. transport of free AA via a bunch of different transporters and di-/ tri- also through variety of transporters.
Do not need to know image
sodium-dependant AA transport
- sodium binds to amino acid transporter
- binding of Na+ increases the carriers affinity for the AA which them binds to the carrier
- A sodium-amino acid-cotransporter forms
- conformational change in the complex occurs and results in the delivery of the sodium and amino acid into the cytosol of the intestinal cell
- Sodium is pumped out of the cell by a Na+/K+ATPase
When is the sodium-dependant AA transport important?
quantitatively important when [AA] is low
what other cells use the Na+ dependant transport system?
- enterocytes of SI
- liver
- kidneys
AA acid distribution once in the SI
- most AA is abosrbed in the jejunum and goes into the hepatic vein for first entry through the liver and then available for systemic circulation
- some might get fermented in the LI
- some is excreted through the feces
Factors that affect the rate of protein digestion/ absorption
- structure affects the rate of diggestion such as fast vs. slow protein (e.g. whey vs. casein)
- food matrix (e.g. fibre)
- oligopeptides vs. free AA
- neutral (easier) before basic or acidic
- essential before non-essential
How does the SI regulate amino acid absorption?
adaptively regulates its capacity by:
1. change in absorptive surface area: hyperplasia/hypertrophy associated with obesity/diabetes/pregnancy/lactation
2. change in individual enteroctytes: gene expression of amino-peptidases and membrane transporters
What happens with SI regulation of AA absorption with TPN?
total parental nutrition which is a method that completely bypasses the GI tract and leads to intestinal atrophy and reduced absorptive capacity of the intestine
Why are are intact proteins generally not absorbed?
Too big
* brush border proteases prevent it, because they break them down first
* no transporters on basolateral membrane for proteins
* proteins cannot permeat through entercyte tight junctions
What is the exception to intact proteins being absorbed?
newborns due to leakiness of the tight junctions, but eventually these close up
* possible for leakiness in adults as well
What is important for newborns to have right away for a good protein source?
colostrum
* provides nutrients for growth
* immunoglobulins (antibodies) for protection
* growth factors that promotoe maturation of the infants GI tract
Benefit of colostrum for adults
- positive effects on GIT
- protein source
- lactose free
- proline rich
What happens in celiac disease?
Gliadin disrupts tight junctions between intestinal epithelial cells so that protease resistant peptides of gliadin can enter the circulation to induce an immune response which causes damage to the membrane allowing in more large peptides
Role of enterocytes in AA absorption & availability
free AAs pass through into enterocyte unmetabolized
* can be used for protein synthesis in the enterocyte
* some is partially or completely oxidzied and used for energy
* intermediary metabolic conversion of AAs into other AAs or metabolites which are transported out
What AAs in the enterocytes are often used for energy?
the SI mainly uses Glu, Gln and Asp for energy, moreso than glucose
what is Thr used for in the SI?
mucosal protein synthesis (mucin)
What are some metabolic conversions that happen in the enterocytes?
- Gln converted to Ala, Pro, citrulline & ammonia;
- Glu to glutathione, Pro & Arg
- Phe hydroxylated to Tyr
overall absorption of AAs in the enterocytes
- most essential AAs are absorbed into portal transport
- Gln, Glu, Asp little absorbed into portal vein, mostly used for SI energy
- A lot of AAs are metabolically converted to alanine
Conditions of protein malabsorption
- Severe pancreatic dysfunction
- Extensive intestinal resection
- Severe chronic malnutrition
Severe pancreatic dysfunction
pancreas is unable to make enough of the enzymes needed to protein digestion
Extensive intestinal resection
decreased absorbtive surface area due to inability of SI the synthesize protein for itself
Severe chronic malnutrition
nutritional deprivation
Summary of protein digestion
