Bez nadpisu

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Játra a pankreas
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Alcohol dehydrogenase
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Peroxisome
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Bilirubin Metabolism
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Bilirubin Metabolism
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The spleen serves two major functions in the
body 1. It is responsible for the destruction
of old red blood cells. 2. It is a major site
for mounting the immune response.
The spleen
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Erythrocytes Destruction Life span of
erythrocytes varies in different species. The
average is close to 90 days. When they become
fragile, they are removed by the cells of
Mononuclear Phagocytic System (MPS) in the
spleen, liver and bone marrow. When the cells
are phagocytosed, they rupture and disintegrate.
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Gastrointestinal Circulation
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Anatomy of the Biliary System
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Enterohepatic Circulation of the Bile
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Heinrich Otto Wieland 1877 - 1957 The Nobel
Prize in Chemistry 1927 "for his investigations
of the constitution of the bile acids and related
substances" 
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Cholic acid - facilitates emulsification of
fats- a bile salt manufactured in the liver.
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Duodenum Lipase breaks down fat into glycerol and
fatty acids. Amylase breaks downstarch
into maltose, a disaccharide sugar. Trypsin and
chymotrypsin split proteins into polypeptides and
peptides.
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Micelle
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Bile acids form micelles which facilitate the
transport of fatty acids and monoglycerides as
well as other fat soluble compounds from the
intestinallumen to the surface of the enterocyte.
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The products of fat digestion pass by simple
diffusion into the enterocyte where they are
reconstituted into triglycerides and formed into
chylomicrons.
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Liver Cirrhosis
Normal Liver
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Frederick Banting 1891- 1941Charles Best 1899-
1978
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Drs. Banting and Best In The Laboratory
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Insulin
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• The concentration of glucose in the blood rises
  rapidly after the ingestion
• of glucose (or a high carbohydrate meal).
• The increase in blood glucose concentration is
  closely followed in time
• by an increase in plasma insulin concentration.
• Peak glucose concentration occurs within the
  first hour and a return
• to basal levels within two hours.

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• 1) The initial increase in glucagon concentration
  parallels the increase in glucose.
• 2) The glucagon concentration begins to fall
  shortly after glucose concentration begins to
  rise.
• 3) After blood glucose and insulin levels return
  to normal, the concentration of glucagon begins
• to increase again back towards basal levels.

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The Insulin Receptor
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1) Glucose enters the cells of the body through
glucose transporter (GLUT) proteins which are
embedded within the cell membrane. This is a
process called facilitated diffusion. 2) When
insulin binds to it's receptor, the intracellular
domain of the receptor changes shape
slightly. This sets off a chain of reactions.
These reactions serve to activate certain
enzymes. 3) As a result, more glucose
transporter proteins are released from
intracellular stores and move to the plasma
membrane and become embedded within it.
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The Metabolic Effects of Insulin
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The Metabolic Effects of Glucagon
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The pancreas is a mixed exocrine and endocrine
organ.
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Pancreatic enzymes

• ? Proteins digested by
• ? trypsinogen (inactive) ? trypsin (active)
• (activated by enterokinase or trypsin on cell
  surface of enterocytes)
• ? cleaves basic amino acids
• ? chymotrypsinogen ? chymotrypsin
• ? cleaves aromatic amino acids
• ? proelastase ? elastase
• ? cleaves aliphatic amino acids
• ? procarboxypeptidase ? carboxypeptidase
• ? cleaves single amino acids at carboxy
  terminal
• Starch digested by
• ? amylase
• ? Fats digested by
• ? lipase
• ? hydrolyses triglycerides into fatty acids and
  2-monoglycerides
• ? requires colipase to allow hydrophilic lipase
  into micelle
• ? phospholipase A

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Protease

• There are several classes of
• proteolytic enzymes.
• Serine proteases include digestive
• enzymes trypsin, chymotrypsin, elastase.
• Different serine proteases differ in substrate
  specificity. For example
• Chymotrypsin prefers an aromatic side chain on
  the residue whose carbonyl carbon is part of the
  peptide bond to be cleaved.
• Trypsin prefers a positively charged Lys or Arg
  residue at this position. 

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Trypsin - cleaves basic amino acids
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Trypsinogen could be either activated into
active trypsin either by the brush-border enzyme
enterokinase in the small intestine or
by cathepsin B, a lysosomal enzyme present in
acinar cells. Another mechanism of trypsinogen
activation, which is a unique feature of human
trypsinogen, consists of trypsinogen
autoactivation (Pancreatitis).
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Endopeptidase An enzyme that catalyzes the
cleavage of then internal peptide bonds within a
polypeptide or protein. Exopeptidase An enzyme
that catalyzes the cleavage of the terminal
(last) or next-to-last peptide bond from a
polypeptide or protein, releasing a single amino
acid or dipeptide.
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Chymotrypsin - cleaves aromatic amino acids
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Elastase - cleaves aliphatic amino acids
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• During catalysis, there is nucleophilic attack of
  the hydroxyl O of a serine residue of the
  protease on the carbonyl C of the peptide bond
  that is to be cleaved.
• An acyl-enzyme intermediate is transiently
  formed.
• In this diagram a small peptide is shown being
  cleaved, while the usual substrate would be a
  larger polypeptide.

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• Hydrolysis of the ester linkage yields the second
  peptide product.

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The active site in each serine protease includes
a serine residue, a histidine residue, an
aspartate residue.

• During attack of the serine hydroxyl oxygen, a
  proton is transferred from the serine hydroxyl to
  the imidazole ring of the histidine, as the
  adjacent aspartate carboxyl is H-bonded to the
  histidine.

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• Aspartate proteases include
• the digestive enzyme pepsin
• Some proteases found in lysosomes
• the kidney enzyme renin
• Two aspartate residues participate in acid/base
  catalysis at the active site.
• In the initial reaction, one aspartate accepts a
  proton from an active site H2O, which attacks
  the carbonyl carbon of the peptide linkage.
• Simultaneously, the other aspartate donates a
  proton to the oxygen of the peptide carbonyl
  group.

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• Zinc proteases (metalloproteases) include
• digestive enzymes carboxypeptidases
• matrix metalloproteases (MMPs), secreted by cells
• one lysosomal protease.
• Some MMPs (e.g., collagenase) are involved in
  degradation of extracellular matrix during tissue
  remodeling.
• Some MMPs have roles in cell signaling relating
  to their ability to release cytokines or growth
  factors from the cell surface by cleavage of
  membrane-bound pre-proteins.

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Carboxypeptidase - cleaves single amino acids at
carboxy terminal
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A zinc-binding motif at the active site of a
metalloprotease includes two His residues whose
imidazole side-chains are ligands to the Zn.
Colors in Carboxypeptidase image at right Zn,
N, O.

• During catalysis, the Zn promotes nucleophilic
  attack on the carbonyl carbon by the oxygen atom
  of a water molecule at the active site.
• An active site base (Glu in Carboxypeptidase)
  facilitates this reaction by extracting H from
  the attacking H2O.

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• Cysteine proteases have a
• catalytic mechanism that involves
• a cysteine sulfhydryl group.
• Deprotonation of the cysteine SH by an adjacent
  His residue is followed by nucleophilic attack of
  the cysteine S on the peptide carbonyl carbon. 
• A thioester linking the new carboxy-terminus to
  the cysteine thiol is an intermediate of the
  reaction (comparable to acyl-enzyme intermediate
  of a serine protease).

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• Cysteine proteases
• Papain is a well-studied plant cysteine protease.
  
• Cathepsins are a large family of lysosomal
  cysteine proteases, with varied substrate
  specificities.
• Caspases are cysteine proteases involved in
  apoptosis (programmed cell death). A caspases
  cleave on the carboxyl side of an Asp.
• Calpains are Ca -activated cysteine proteases
  that cleave intracellular proteins involved in
  cell motility and adhesion. They regulate
  processes such as cell migration and wound
  healing.

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• Activation of proteases
• Most proteases are synthesized as larger
  pre-proteins. During activation, the pre-protein
  is cleaved to remove an inhibitory segment.
• In some cases activation involves removal of an
  inhibitory protein.
• Activation may occur after a protease is
  delivered to a particular compartment within a
  cell or to the extracellular milieu. 

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• Lipase
• a fat-splitting enzyme that converts
• fat into fatty acids and glycerin

• The body produces three different forms of
  lipase
• Pharyngeal lipase is produced in the mouth
• and is most active in the stomach.
• Hepatic lipase is produced by the liver
• and regulates the level of fats (lipids) in the
  blood.
• ? Pancreatic lipase is produced by the pancreas
• and released into the duodenum.

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Phospholipase - digests phospholipids
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Cholesterol esterase - produces free cholesterol
from cholesterol esters
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Amylase- a complex sugars -splitting enzyme
that converts complex sugars into simple sugars
There are two kinds of amylase enzymes ?
Alpha-amylase (ptyalin), which is produced by
the salivary glands. This enzyme begins starch
digestion in the mouth and continues to work in
the stomach. ? Pancreatic amylase, which is
secreted by the pancreas into the small
intestine. This enzyme continues the starch
digestion process.
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Ribonuclease- digest RNA
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