METABOLISM OF METABOLISM OF CARBOHYDRATES: CARBOHYDRATES:

DIGESTION OF CARBOHYDRATES. DIGESTION OF CARBOHYDRATES. SYNTHESIS AND DEGRADATION OF SYNTHESIS AND DEGRADATION OF

GLYCOGENGLYCOGEN

DIGESTION OF CARBOHYDRATESDIGESTION OF CARBOHYDRATES

Glycogen, starch and disaccharides (sucrose, lactose and maltose) are hydrolyzed to monosaccharide units in the gastrointestinal tract.The process of digestion starts in the mouth by the salivary enzyme –amilase.

The time for digestion in mouth is limited.

Salivary -amilase is inhibited in stomach due to the action of hydrochloric acid.

Another -amilase is produced in pancreas and is available in the intestine.

-amilase hydrolyzes the -1-4-glycosidic bonds randomly to produce smaller subunits like maltose, dextrines and unbranched oligosaccharides.

-amilase

The intestinal juice contains enzymes hydrolyzing disaccharides into monosaccharides (they are produced in the intestinal wall)

Sucrase hydrolyses sucrose into glucose and fructose

Sucrose

sucrase

Fructose

Glucose

Lactose

lactase

Maltase hydrolyses maltose into two glucose molecules

Lactase hydrolyses lactose into glucose and galactose

Maltose

maltase

Galactose Glucose

GlucoseGlucose

ABSORPTION OF ABSORPTION OF CARBOHYDRATESCARBOHYDRATESOnly monosaccharides are absorbed

The rate of absorption: galactose > glucose > fructoseGlucose and galactose from the intestine into

endothelial cells are absorbed by secondary active transport

Na+ GlucoseProtein

Protein

Carrier protein is specific for D-glucose or D-galactose.

L-forms are not transported.

There are competition between glucose and galactose for the same carrier molecule; thus glucose can inhibit absorption of galactose.

Fructose is absorbed from intestine into intestinal cells by facilitated diffusion.

Absorption of glucose from intestinal cells into bloodstream is by facilitated diffusion.

Transport of glucose from blood into cells of different organs is mainly by facilitated diffusion.

The protein facilitating the glucose transport is called glucose transporter (GluT).

GluT are of 5 types.

GluT2 is located mainly in hepatocytes membranes (it transport glucose into cells when blood sugar is high);

GluT1 is seen in erythrocytes and endothelial cells;

GluT3 is located in neuronal cells (has higher affinity to glucose);

GluT5 – in intestine and kidneys;

GluT4 - in muscles and fat cells.

In the well-fed state the glucose after absorption is taken by liver and deposited as a glycogen

Glycogen is a very large, branched polymer of glucose residues that can be broken down to yields glucose molecules when energy is needed

Most glucose residues in glycogen are linked by a-1,4-glyco-sidic bonds, branches are created by a-1,6-glycosidic bonds

GLYCOGEN SYNTHESIS AND DEGRADATION

Liver (10 % of weight) and skeletal muscles (2 %) – two major sites of glycogen storage

Glycogen is stored in cytosolic granules in muscle and liver cells of vertebrates

Glycogen serves as a buffer to maintain blood-glucose level. Stable blood glucose level is especially important for brain where it is the only fuel. The glucose from glycogen is readily mobilized and is therefore a good source of energy for sudden, strenuous activity.

Glucose-6-phosphate is the central metabolite in the synthesis and decomposition of glycogen.

In the well-fed state glucose is converted to glucose-6-phosphate, which is the precursor for the glycogen synthesis.

The glucose-6-phosphate derived from the breakdown of glycogen has three fates: (1) glycolysis; (2) pentose-phosphate pathway; (3) convertion to free glucose for transport to another organs.

Glycogenolysis - degradation of glycogen The reaction to release glucose from polysaccharide is not simple hydrolysis as with dietary polysaccharides but cleavage by inorganic phosphate – phosphorolytic cleavage

Phosphorolytic cleavage or phosphorolysis is catalyzed by enzyme glycogen phosphorylase

There are two ends on the molecules of starch or glycogen: a nonreducing end (the end glucose has free hydroxyl group on C4) and a reducing end (the end glucose has an anomeric carbon center (free hydroxyl group on C1)

DEGRADATION OF GLYCOGEN

Glycogen phosphorylase removes glucose residues from the nonreducing ends of glycogen

Acts only on a-1-4 linkages of glycogen polymer

Product is a-D-glucose 1-phosphate (G1P)

Cleavage of a glucose residue from the nonreducing end of glycogen

•GP is a dimer of identical subunits (97kD each)

•Catalytic sites are in clefts between the two domains of each subunit

•Binding sites for glycogen, allosteric effectors and a phosphorylation site

•Two forms of GP

Phosphorylase a (phospho- rylated) active form

Phosphorylase b (dephospho- rylated) less active

Structure of glycogen phosphorylase (GP)

• GP catalyzes the sequential removal of glucose residues from the nonreducing ends of glycogen

• GP stops 4 residues from an a 1-6 branch point

• Tranferase shifts a block of three residues from one outer branch to the other

• A glycogen-debranching enzyme or 1,6-glucosidase hydrolyzes the 1-6-glycosidic bond

• The products are a free glucose-1-phosphate molecule and an elongated unbranched chain

•Phosphoglucomutase catalyzes the conversion of G1P to glucose 6-phosphate (G6P)

Metabolism of Glucose 1-Phosphate (G1P)

Glycogen Synthesis

•Synthesis and degradation of glycogen require separate enzymatic steps

•Cellular glucose converted to G6P by hexokinase

•Three separate enzymatic steps are required to incorporate one G6P into glycogen

•Glycogen synthase is the major regulatory step

•Phosphoglucomutase catalyzes the conversion of glucose 6-phosphate (G6P) to glucose 1-phosphate (G1P).

Glucose 1-Phosphate formation

UDP-glucose is activated form of glucose.

UDP-glucose is synthesized from glucose-1-phosphate and uridine triphosphate (UTP) in a reaction catalized by UDP-glucose pyrophosphorylase

Glycogen synthase adds glucose to the nonreducing end

of glycogen

A branching enzyme forms -1,6-linkagesGlycogen synthase

catalyzes only -1,4-linkages.

The branching enzyme is required to form -1,6-linkages.

Branching is important because it increases the solubility of glycogen.

Branching creates a large number of terminal residues, the sites of action of glycogen phosphorylase and synthase.

•Muscle glycogen is fuel for muscle contraction

•Liver glycogen is mostly converted to glucose for bloodstream transport to other tissues

•Both mobilization and synthesis of glycogen are regulated by hormones

•Insulin, glucagon and epinephrine regulate mammalian glycogen metabolism

Regulation of Glycogen Metabolism

•Insulin is produced by b-cells of the pancreas (high levels are associated with the fed state)

•Insulin increases rate of glucose transport into muscle, adipose tissue via GluT4 transporter

•Insulin stimulates glycogen synthesis in the liver via the second messenger phosphatidylinositol 3,4,5-triphosphate (PIP3)

Hormones Regulate Glycogen Metabolism

Insulin

Glucagon

•Secreted by the a cells of the pancreas in response to low blood glucose (elevated glucagon is associated with the fasted state)

•Stimulates glycogen degradation to restore blood glucose to steady-state levels

•Only liver cells are rich in glucagon receptors and therefore respond to this hormone

Epinephrine (Adrenalin)

•Released from the adrenal glands in response to sudden energy requirement (“fight or flight”)

•Stimulates the breakdown of glycogen to G1P (which is converted to G6P)

•Increased G6P levels increase both the rate of glycolysis in muscle and glucose release to the bloodstream from the liver and muscles

•Both liver and muscle cells have receptors to epinephrine

Effects of hormones on glycogen metabolism

•Glycogen phosphorylase (GP) and glycogen synthase (GS) control glycogen metabolism in liver and muscle cells

•GP and GS are reciprocally regulated both covalently and allosterically (when one is active the other is inactive)

•Covalent regulation by phosphorylation (-P) and dephosphorylation (-OH)

•Allosteric regulation by glucose-6-phosphate (G6P)

Reciprocal Regulation of GlycogenPhosphorylase and Glycogen Synthase

COVALENT REGULATION

Active form “a” Inactive form “b”

Glycogen phosphorylase -P -OH

Glycogen synthase -OH -P

Reciprocal Regulation of GP and GS

ALLOSTERIC REGULATION by G6P

GP a (active form) - inhibited by G6PGS b (inactive form) - activated by G6P

Activation of GP and inactivation of GS by Epinephrine and Glucagone

Activation of GS and inactivation of GP by Insulin