Monday, August 20, 2012

Carbohydrate Metabolism

Metabolism is the sequence of reactions proceeding inside our body involving synthesis (anabolism), breakdown (catabolism) and conversion of various compounds.
Anabolism: it is the synthesis of various compounds.
Catabolism it is the breakdown of various compounds.

Digestion of Carbohydrates
Carbohydrates in diet include:
1.             Monosaccharides: Need no digestion
  1. Glucose = Grape sugar (present in grapes).
  2. Fructose = Fruit sugar (present in fruits and honey).
2.             Disaccharides:
  1. Lactose = Milk sugar
  2. Maltose = Malt sugar (present in cereals).
  3. Sucrose = cane sugar and molasses (العسل الأسود)
3.             Polysaccharides:
a-    Starch = Plant polysaccharide. Formed from amylose (unbranched chains, a1-4 glucosidic linkages) and amylopectin (highly branched chains, a1-4 and a1-6 glucosidic linkages at the branch points)
b-    Glycogen = Animal starch. Formed from highly branched chains, similar to amylopectin of starch.
c-    Cellulose = Structural polysaccharides in plants formed from unbranched chains of b-glucose molecules that are attached together by b-1,4 glucosidic bonds. This type of bonds can not be digested by the human being due to absence of b 1-4 glucosidase (NO b- AMYLASE). Undigested cellulose (dietary fibers) increases intestinal bulk and prevents constipation.
Carbohydrate digestion:
In the mouth:
¨          By Salivary amylase = a-amylase.
In the stomach: Salivary amylase is inhibited by the low pH in the stomach caused by HCl (pH = 1-2)
In the intestine: Major digestion of carbohydrate occurs in the small intestine by the following enzymes:
1.     Intralumenal digestion by Pancreatica amylase
2.     Hydrolysis on the surface of the brush border of small intestine:
    1. Maltase (glucoamylase, exo 1,4 a D glucosidase): it catalyzes the hydrolysis of maltose.
    2. Sucrase: it catalyzes the hydrolysis of a 1,2 linkage of sucrose.
    3. Lactase: it hydrolyzes the b 1,4 galactosidic linkage of lactose.
N.B. The end products of carbohydrate digestion include: D-Glucose, D-fructose, and D-galactose.
Disorders of Carbohydrate Digestion
1- Lactose intolerance (lactase deficiency):
A clinical disorder results from lactase deficiency.
  1. Primary lactase deficiency: Due to genetic defect leading to low levels of enzyme.
  2. Secondary lactase deficiency due to injury to the intestinal mucosa by inflammation (gastroenteritis) or by surgical removal.
Clinical picture:
¨          Abdominal colicمغـــص, flatulence, and distensionاتنفـــــاخ that result from fermentation of lactose by intestinal bacteria with the release of gases such as CO2 and H2.
¨          Diarrhea اسهـــال due to accumulation of lactose and the products of bacterial fermentation, which are osmotically active compounds. These compounds cause withdrawal of water resulting in diarrhea.
¨   Treatment of the cause if present e.g. treatment of gastroenteritis.
¨   Lactose free milk (milk that does not contain lactose).
¨   Yougort can replace milk as it has low contents of lactose.
Fate of Absorbed Monosaccharides:
¨          Fructose and galactose are transported by portal blood to the liver, where they are converted to glucose.
¨          Absorbed glucose is transported to the liver by portal blood, then by systemic circulation to the different tissues.
¨          In the hepatic cellsglucose is phosphorylated by glucokinase enzyme to give glucose-6-phosphate. Such phosphorylation has two functions:
1.                Activation of glucose to be utilized by different pathways.
2.                Trapping of glucose in the cells.
¨   Some glucose will escape from glucokinase effect and enter the systemic circulation to be utilized by extrahepatic tissues (all other body tissues).

Definition and site:
§ Glycolysis is a metabolic pathway for breakdown of glucose.
§ In glycolysis glucose (6C) is cleave to give 2 molecules of pyruvic acid or lactic acid (3C).
§ It occurs in all tissues under both aerobic and anaerobic conditions.
§ All enzymes of glycolysis are present in the cytosol.
Steps: Ten enzymatic reactions to end by pyruvate.

The End Products of Glycolysis
The end products of glycolysis are:
a.    2 ATP.
b.    2 Pyruvate.
c.    2 NADH + H+.
The fate of pyruvate and NADH will differ under aerobic and anaerobic conditions.
Glycolysis under aerobic conditions
a.        Pyruvate enters the mitochondria where it is oxidatively decarboxylated to active acetate (acetyl CoA). Active acetate is then can enter in TCA cycle or give rise to other compounds such as fatty acids, cholesterol, etc. 
b.        Each NADH is oxidized in the respiratory chain and generates about 3 ATP               
 Under anaerobic conditions:
NADH + H+ is utilized to reduce pyruvate to lactate in order to regenerate the oxidized coenzyme (NAD). Lactate Dehydrogenase (LDH) is the enzyme catalyzing the reaction.
                          Pyruvate                                                           Lactate
                                              NADH+H+             NAD

Lactate is always the end product of glycolysis in:
·         Red blood cells because they lack mitochondria.
·         Vigorously Exercising muscles because of the hypoxia.
·         Glycolysis in tumor cells because:
1.    Hypoxia due to short blood supply.
2.    Small number of mitochondria.
3.    Over production of glycolytic enzymes.
4.    Production of an isoenzyme of hexokinase, which is not inhibited by glucose 6-phosphate.
Energy Produced in Glycolysis
1- Anaerobic Glycolysis:
·         Two molecules of ATP are gained for each molecule of glucose converted to lactate.
·         Two molecules of lactate are produced for each glucose molecule metabolized.
ATP Gained
ATP Lost
     2 ATP at reaction 7                            
One ATP at reaction 1
     2 ATP at reaction 10                          
One ATP at reaction 3
     4 ATP   are gained                                
2 ATP are lost.
Thus, the net gain in anerobic glycolysis is 2 ATP.
2.     Aerobic Glycolysis:
Net gain of ATP = 6 to 8 ATP molecules for every molecule of glucose converted to pyruvate.
             ATP Gain                                                        
ATP Lost
2 NADH + H+ are gained in reaction 6.
When reoxidized in the ETC:
2 X 3 ATP = 6 ATP
or 2X2 ATP = 4 ATP depending on the shuttle used.
One ATP at reaction 1
One ATP at reaction 3
2 ATP at reaction 7                                            
2 ATP at reaction 10.

Total gain under aerobic conditions = 8 to 10 ATP.
Total ATP lost 2 ATP
Net ATP gained under aerobic conditions = 6 to 8 ATP
Comparison between aerobic and anaerobic glycolysis

End product
6 to 8 ATP
Only 2 ATP
Oxidation of NADH+H+
Respiratory chain in mitochondria
Lactate formation
Importance of Glycolysis
1-     An important source of energy  under anaerobic conditions especially for:
·         RBCs due to lack of mitochondria.
·         Cornea, lens, regions of retina, leucocytes, testis, and renal medulla with non functioning mitochondria due to decreased blood supply.
·         Muscles during strenuous exercise due to hypoxia.
2-     Under aerobic conditions, glycolysis is a preparatory pathway for complete oxidation of glucose through Krebs cycle and ETC. It is essential to provide energy required by vital organs e.g. heart and brain.
3-     It is the main pathway for metabolism of dietary fructose, and galactose.
4-     Synthetic functions:
·         Synthesis of serine from 3- phosphoglycerate.
·         Synthesis of glycerol 3-phosphate from dihydroxyacetone phosphate. Glycerol 3 phosphate enters in the synthesis of triacylglycerols and phospholipids.
DHAP                                     Glycerol 3-Phosphate
Pyruvate                                 Active Acetate      FA                        Triacylglycerols
5Glycolysis is important during birth. During delivery, the blood supply to most tissues decrease except the brain. During this period, tissues will depend upon glycolysis for supply of energy until circulation returns to normal.
5-     Essential part for gluconeogenesis (reversal of glycolysis). See later.
6-     Important for production of 2,3 Diphosphoglycerate (2,3 DPG) in RBCs.

Glycolysis in Red Blood Cells
I- Energy Production in RBCs:
q  Mature RBCs have no mitochondria, thus they have no TCA cycle and no respiratory chain.
q  Largely dependent on glycolysis for production of energy.
q  Glycolysis in RBCs always terminates with lactic acid.
q  The net ATP gained in RBCs is 2 ATP.
q  Reduced NADH+H+ is oxidized to NAD by Lactate Dehydrogenase (LDH) enzyme.

                   O                                                                                   OH
           CH3-C- COOH                                       LDH              CH3- CH-COOH
            Pyruvate                                                                             Lactate
                                              NADH+H+             NAD
Lactate produced by RBCs and other anaerobic tissues is released to the circulation to be taken by either the liver or the heart
II- Rapoport-Luebering (R-L) cycle in RBCs:
¨       It is a side pathway from glycolysis in red blood cells.
¨       By this cycle the high-energy phosphate in position one of 1,3 diphosphoglycerate is lost by conversion to 2,3 bisphosphoglycerate (2,3 BPG). This will result in lowering ATP production by 2 ATP/ one molecule of glucose i.e a net Zero ATP production.
Importance of 2,3 Bisphosphoglycerate (2,3 BPG) to Red Blood Cells:
q    2,3 DPG binds to hemoglobin to reduce its affinity towards oxygen i.e. increasing oxygen dissociation and delivery to tissues.
q    2,3 DPG binds non-covalently to the b subunits of hemoglobin molecule, shifting it from the relaxed ® to the taut (T) form.
q    The T form of hemoglobin has lower affinity towards O2 than the R form.
q    Stored blood may have a lower levels of 2,3 DPG.
q    In blood banks, Inosine is added to the stored blood.
q    Inosine is converted inside the RBCs into 2,3 DPG, keeping its normal levels.
q    2,3 DPG levels increase with tissue hypoxia.
q    2,3 DPG levels increase in persons suffering from pyruvate kinase deficiency. Thus the affinity of hemoglobin to oxygen is less than normal in such conditions
q    2,3 DPG levels decrease in hexokinase deficiency, so affinity of hemoglobin to oxygen is increased.
Sources and Fate of Pyruvate

                                Malic enzyme
Malate + NADP                                 Pyruvate + CO2 + NADPH+H+ 

      Serine Cysteine, Glycine,    Glycolysis        Malate           Alanine

                    Deamination                                      Transamination
                                                                        lactate dehydrogenase
 Glycerol                                Pyruvate                              Lactate.
1.   From glucose by glycolysis.
2.   From glycerol of lipids through formation of glycerol phosphate then dihydroxyacetone phosphate then glyceraldehyde 3 phosphate then through glycolysis will give rise to pyruvate.
3.   From amino acids by transamination and deamination (see protein metabolism)
4.   From lactate by lactate dehydrogenase.
5.   From malate by malic enzyme
Fate of Pyruvate:
1.    Converted to lactate by lactate dehydrogenase.
2.    Converted to active acetate inside the mitochondria by pyruvate dehydrogenase.
3.    Converted to oxaloacetate by pyruvate carboxylase enzyme inside the mitochondria.
§  Oxaloacetate can be used for the synthesis of:
§  Citrate (in TCA cycle) when combined with acetyl CoA.
§  Aspartate when transaminated.
§  Glucose by the process of gluconeogenesis.

Cycles for Glucose Utilization and Their Sites inside the Cell:
1.     Carbohydrate Cycles in the Cytosol:
§  Glycolysis. In the cytosol of the liver and all other tissues.
§  Hexose Monophosphate (HMP) Pathway. In the liver and tissues that require NADPH+H+ for the synthesis of fatty acids, cholesterol and steroid hormones i.e adipose tissue and suprarenal glands.
§  Glycogenesis = synthesis of glycogen. In the liver and muscles.
§  Glycogenolysis = break down of glycogen to glucose 6-phosphate (in the muscles) and glucose (in the liver).
§  Uronic acid pathway = synthesis of glucuronic acid. In the liver.
2.     Carbohydrate Cycles in the Mitochondria:
§  Krebs cycle. In cells having mitochondria.
3.     Carbohydrate Cycles in Both Cytosol and Mitochondria;
§  Gluconeogenesis = synthesis of glucose from non-carbohydrate sources.

Best Wishes: Dr.Ehab Aboueladab, Tel:01007834123, ehab fathy aboueladab
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