Cho .ppt

Chemistry of Carbohydrates All CHO contain C O &OH-functional groups & are classified into: 1-Monosaccharides 2-Disaccharides 3-Oligosaccharides 4-Polysaccharides

Monosaccharides

*Simple sugar. *Trioses, tetroses, pentoses, hexoses….*Aldoses or ketoses. *Most important are hexoses like glucose, galactose & fructose.*Stereoisomer property which could be D or L.

Disaccharides

Products of chemical reaction between 2 monosaccharides linked by glycosidic link with loss of a molecule of water . *Maltose (glucose + glucose) ..Reducing. *Lactose (glucose + galactose ) ..Reducing. *Sucrose (glucose + fructose). .. Non Reducing.

Oligosaccharides

Products of condensation of 3-10 monosaccharide units as in maltotriose.

Polysaccharides

Products of condensation >10 monosaccharide units. *Starch- Plant origin consist of amylose (α-1, 4-glucosidic linkages) +amylopectin (α-1, 4-glucosidic linkages + α-1, 6-branched glucosidic linkages). *Glycogen-Animal origin, it has structure similar to amylopectin.

Fate of Carbohydrates

*Glucose is the only CHO to be directly used. *Galactose & fructose mainly converted to glucose in the liver. *Pentoses( xylose, arabinose& ribose) are important in nucleotides, nucleic acids & several coenzymes. CHO(mainly glucose) is a main source of human energy & it is a unique source to some tissues as nervous system & RBC.



After absorption glucose is converted to glucose-6 phosphate inside the cells which may follow one of the following pathways. 1-Glycolysis… Energy.2-Hexose monophosphate shunt {phosphogluconate oxidative pathway, pentose phosphate pathway}...Nucleotide synthesis.3-Glycogenesis... Storage.

Glycolysis [Embden-Meyerhof pathway]

*Major pathway for glucose metabolism, occurs in the cytosol of all cells. Its unique in that it can function either aerobically or anaerobically. *Anaerobic conditions are important in RBC &skeletal muscle in anoxic episodes (unlike heart muscle).

Reaction 1: Phosphate Ester Synthesis

Reaction 2: Isomerization

Reaction 3: Phosphate Ester Synthesis

Reaction 4: Split Molecule in half

Reaction 5: Oxidation/Phosphate Ester Synthesis

 Reaction 6: Hydrolysis of Phosphate; Synthesis of ATP

Reaction 7: Isomerization

Reaction 8: Alcohol Dehydration (Enolation)

Reaction 9: Phosphate Ester Hydrolysis, Synthesis of ATP

Fate of Pyruvate
Aerobic condition
Anaerobic condition

Conclusion

*Glucose+2NAD++2ADP+2P 2 pyruvate+2ATP+2NADH+2H+ *ATP produced :- A-Anaerobic:2ATP{2ATP(reaction 6)+2ATP(reaction 9) 2ATP (reactions 1&3)}. B-Aerobic :- 2 ATP as in anaerobic conditions. + 5 ATP from two NADH2+ (reaction 5). +5 ATP from two NADH2+(conversion of pyruvate into acetyl-CoA). + 20 ATP (citric acid cycle). Therefore the total = 32 ATP. *3 Reactions ((1, 3& 9)) are irreversible regulating glycolysis . *Glycolysis blocked by iodoacetate(reaction5)& fluoride(reaction8)

High-energy electrons carried by NADH

GLYCOLYSIS
Glucose
Pyruvicacid
KREBSCYCLE
ELECTRONTRANSPORT CHAINAND CHEMIOSMOSIS
Mitochondrion
Cytoplasmicfluid

Clinical Aspects

1- Lactic Acidosis:- A-Arsenite inhibit pyruvate dehydrogenase complex. B-Thiamin deficiency inhibit pyruvate dehydrogenase complex. C-Inherited pyruvate dehydrogenase deficiency. 2- Inherited aldolase& pyruvate kinase deficiency in RBC cause hemolytic anemia. 3-Muscle phosphofructokinase deficiency cause low exercise capacity 4- Competition of arsenate with inorganic phosphate give l-arseno-3-phosphoglycerate that hydrolyze to give 3-phosphoglycerate + heat, without generating ATP.

Citric Acid Cycle {Krebs cycle,Tricarboxylic Acid Cycle}

* Series of reactions discovered by Hans Krebs in 1937 occur in the mitochondria that oxidize acetyl-CoA to CO2 +H2O & production of reducing equivalents that upon reoxidation in the respiratory chain ATP are formed. * It is dependant on oxygen availability.

Overview of Acetyl Co- A metabolism

1-At the confluence of the major metabolic pathways ((carbohydrate, lipid & protein)). 2-Source of acetyl units in the anabolic processes responsible for synthesis of long chain fatty acids , cholesterol , steroid & ketone bodies . 3-Catabolism of acetyl Co-A in citric acid cycle .

Importance of Citric Acid Cycle

1-Final common pathway for the aerobic oxidation of carbohydrate, lipid & protein . 2-Central role in gluconeogenesis, lipogenesis & interconversion of amino acids. 3-Liberation of much free energy from oxidation of carbohydrate, lipid & protein. 4-Formation of reducing equivalents which enter the respiratory chain for energy production.

Reaction 1: Synthesis of Citrate

Reaction 2: Dehydration & Rehydration

Reaction 3: Dehydrogenation & Decarboxylation

Reaction 4: Oxidation & Decarboxylation

Reaction 5: Hydrolysis of Succinyl-CoA, Synthesis of ATP

Reaction 6: Dehydrogenation

Reaction 7: Hydration

Reaction 8: Dehydrogenation

Energetic of Citric Acid Cycle

Reaction 3 1 NADH2+ 2.5ATP . Reaction 4 1 NADH2+ 2.5ATP . Reaction 5 1ATP. Reaction 6 1 FADH2+ 1.5ATP . Reaction 8 1 NADH2+ 2.5ATP . 10 ATP molecules are produced for each cycle from one molecule of acetyl-CoA.

Regulation of Citric Acid Cycle

1-Proper function of respiratory chain (oxygen , ADP & NAD+). 2-Regulatory reactions ((irreversible or nearly irreversible)) : R1: Synthesis of Citrate. R 3: Dehydrogenation & Decarboxylation. R4:Oxidation & Decarboxylation (Oxidative decarboxylation).

Role of Vitamins in Citric Acid Cycle

(1) Riboflavin (FAD) in reaction 6. (2) Niacin (NAD) in three dehydrogenation reactions (Reactions 3, 4&8). (3) Thiamin) thiamin diphosphate( the coenzyme for α-ketoglutarate dehydrogenase. (4) Pantothenic acid, as part of coenzyme A.

Clinical Aspects

The few genetic defects of citric acid cycle enzymes that have been reported are associated with severe neurological damage as a result of very considerably impaired ATP formation in the central nervous system.

Glycogen metabolism

Glycogen is major CHO storage in animals , present in: 1-liver: represent up to 5% of liver wt, concern with maintenance of blood glucose between meals. After 12-18 hours fasting its almost totally depleted. 2-Muscle: represent up to 0.7% of muscle wt , it is about 3-4 times to that of liver ; source of glucose for glycolysis within the muscle itself.

Metabolisms of glycogen include:- 1-Synthesis (glycogenesis). 2-Degradation (glycogenolysis). These two processes are separated reactions.

Glycogenesis

Glycogenesis is the process of glycogen synthesis, in which glucose molecules are added to chains of glycogen. Glycogenesis depend on the demand for glucose and ATP (energy).

Reaction 1

Reaction 2

Reaction 3

Reaction 4

Reaction 5

Glycogenolysis

Reaction 1

Reaction 2

Reaction 3

Regulation of Glycogen Metabolism

Glycogenesis

Glycogenolysis

Glycogen Storage Diseases ((Glycogenosis))

Generic term describe a group of inherited disorders (Types) characterized by deposition of abnormal type or quantity of glycogen due to partial or complete absence of certain enzymes. Since glycogen enormously large, an inability to degrade it cause cells to become pathologically engorged + functional loss of glycogen.

Hexose monophosphate shunt {phosphogluconate oxidative pathway, pentose phosphate pathway}

Alternative route for glucose metabolism. (1) Formation of NADPH for reduction processes & for synthesis of FA & steroids. )2( Synthesis of ribose for nucleotide & nucleic acid formation

Reactions of Pentose Phosphate Pathway

Occur in the cytoplasm. Sequences of reactions are divided into 2 phases:- 1- Oxidative nonreversible phase. 2-Nonoxidative reversible phase.


Oxidative Nonreversible Phase
Oxidation (dehydrogenation) of glucose 6-phosphate into ribulose 5-phosphate.

Step 1

Step 2

Nonoxidative Reversible Phase

Ribulose 5-phosphate is end in the formation of glucose 6-phosphate .

Step 1

Step 2

Step 3

Step 4

Step 5

Step 5

Although glucose 6-phosphate is common to both pentose phosphate pathway & glycolysis, the pentose phosphate pathway is markedly different from glycolysis by:- 1-Oxidation utilizes NADP rather than NAD. 2-CO2 is a characteristic product of pentose phosphate pathway. 3- No ATP is generated in the pentose phosphate pathway.

Reductive function of NADPH

Glucose-6-Phosphate Dehydrogenase Deficiency ((G6PD Deficiency)) or Favism
Genetic deficiency of G6PD, with consequent impairment of generation of NADPH +H+, common in Mediterranean & Afro-Caribbean. Manifested as hemolytic anemia when subjected to oxidants as primaquine, aspirin, sulfonamides or eaten fava beans. Glutathione peroxidase is dependent upon a supply of NADPH, which in RBC formed only via the pentose phosphate pathway.

Uronic Acid Pathway

Alternative pathway of glucose metabolism, no ATP generated. Catalyzes conversion of glucose into glucuronic acid, pentoses& in animal ascorbic acid. Glucuronic acid (glucuronate) is important in: A-Incorporated into proteoglycans. B- Conjugation of steroid hormones, bilirubin & number of drugs. Pentoses mainly xylulose 5-P enter pentose phosphate pathway. Vitamin C produced in animal while in human & other primates can not synthesized.

Metabolism of other hexoses

Fructose & galactose metabolism

Fructose Metabolism

Small Intestine Fructose Portal Vein Liver Fructose

Glucose Glycolysis F.A

Clinical Aspects of Fructose Metabolism
1) - Loading of liver with fructose :- A-Hyperlipidemia. B-Hyperuricemia & gout. 2)-Essential fructosuria:- lack of hepatic fructokinase. 3)-Hereditary fructose intolerance:- absence of hepatic fructose 1-phosphate aldolase cause- A- Fructose-induced hypoglycemia. B- Hyperuricemia & gout. C-Liver impairment. D-Failure to thrive. Diagnosis by detect fructose in urine & measure enzyme activity. Treatment by diets low in fructose, sorbitol &sucrose.

Galactose Metabolism

Galactose is derived from the intestinal hydrolysis of lactose. It is readily converted in the liver to glucose. Required for the formation of lactose & as a constituent of glycolipids, proteoglycans & glycoproteins.

Galactosemia

Inborn error of metabolism, its caused mainly by defect of galactose 1-phosphate uridyl transferase & to less extent by defect in galactokinase or UDPGal 4-epimerase. Clinical features after baby start sucking milk . 1-Cataract. 2-Failure to thrive. 3-Liver impairment especially in galactose 1-phosphate uridyl transferase deficiency . 4-Hypoglycemia. Diagnosis by detection of galactose in urine. Treatment by galactose-free diets.

Gluconeogenesis

Gluconeogenesis is the term used to include all pathways responsible for converting the noncarbohydrate precursors to the glucose or glycogen. Glucogenic amino acids, lactate& glycerol. Liver & kidney are the major gluconeogenic tissues.


Importance of gluconeogenesis
1-Meets the body need for glucose . 2- Clears lactate produced by muscle & RBC. 3- Clears glycerol produced by adipose tissue. Failure of gluconeogenesis is usually fatal.

Regulation of Gluconeogenesis

Regulation of Gluconeogenesis
Fructose-2, 6-bisphosphate is most potent positive stimulator of glycolysis (( phosphofructokinase)) & inhibitor of gluconeogenesis (( fructose 1, 6 bisphosphatase)).

Regulation of Gluconeogenesis

Hormones regulate gluconeogenesis acting through the enzymes control irreversible reactions of gluconeogenesis (pyruvate carboxylase, Phosphoenolpyruvate carboxykinase, fructose- 1, 6-bisphosphatase & glucose-6-phosphatase). A-Glucocorticoids, glucagon & epinephrine stimulate gluconeogenesis . B-Insulin inhibits gluconeogenesis.

Hormonal Control of Carbohydrate Metabolism

1-Glycolysis is stimulated by insulin & is inhibited by glucagon & epinephrine. 2-Glycogenesis is stimulated by insulin & is inhibited by glucagon & epinephrine. 3-Glycogenolysis is stimulated by glucagon & epinephrine & is inhibited by insulin. 4-Gluconeogenesis is stimulated by glucocorticoids, glucagon & epinephrine & is inhibited by insulin.

Blood Glucose Level

The concentration of blood glucose is regulated within narrow limits ranging from 3.3 mmol/L((60 mg/dL)) in starvation to 7. 2 mmol/L ((130 mg/dL)) after the ingestion of a carbohydrate meal. A sudden decrease in blood glucose will cause convulsions due to the immediate brain dependence on a supply of glucose. However, much lower concentration can be tolerated, provided progressive adaptation is allowed by gluconeogenesis & ketone bodies formation.


Sources of Blood Glucose
I ))-Diet: II ))-Gluconeogenesis: III ))-Glycogenolysis:

Glucosuria

Normally glucose is continuously filtered by the glomeruli but its completely reabsorbed in the renal tubules. This happen when venous blood glucose concentration is below the renal threshold for glucose {171-180 mg/dl (9.5-10.0 mmol/L) } The presence of glucose in urine (glucosuria) suggest: 1-Hyperglycemia. 2- Reduction of renal threshold for glucose as occurs in: A-Renal glucosuria. B-During pregnancy.

Diabetes Mellitus

DM is a family of disorders characterized by hyperglycemia. The disorders of diabetes differ in their etiology , symptoms & in consequences of disease. In Mosul more than 10% of the population suffers from diabetes.

Classification of Diabetes Mellitus

-Type 1 diabetes mellitus. -Type 2 diabetes mellitus. -Gestational diabetes mellitus. -Other specific types of diabetes mellitus.

Type1 Diabetes Mellitus

5-10% of diabetes ,characterized by lack of insulin production & secretion . Manifests during childhood & adolescents. Treatment by insulin replacement, diet & exercise . Subclassified into:- A-Immune mediated B-Idiopathic

A-Immune mediated : -Common form -Autoimmune destruction of β cells by autoantibodies. *Genetic susceptibility for autoantibodies , with certain histocompatibility antigens predominant (HLA-DR3 &DR4) . *Development of disease is complex; triggering factors, as rubella, mumps & other viral infection & chemical contact may be necessary for progression of disease.


B-Idiopathic: Rare form of type 1 diabetes in which there is no any obvious cause for the development of disease.

Type 2 Diabetes Mellitus

Most common type of diabetes. Reduction of cellular effects of insulin ((insulin resistance)) or inability of β cells to produce enough insulin .polygenic hereditary + environmental factors (obesity, lack of physical activity & racial groups) Other factors are previous history of gestational diabetes, increasing age, dyslipidemia & hypertension.Affects obese people older than 40 years.Treatment by weight loss, diet & oral hypoglycemic drugs. Insulin may be prescribed.

Gestational Diabetes Mellitus

Defined as diabetes that is diagnosed for first time during pregnancy. During pregnancy there is insulin resistance. Most pregnant will compensate with increased secretion of insulin; those who are unable to compensate may develop gestational diabetes . Diminished after delivery; however, the individual who has developed gestational diabetes is at higher risk for the development of type 2 diabetes thereafter specially those showing autoantibodies at the time of delivery.

Other Specific Types of Diabetes

Previously called secondary diabetes. include :--Genetic defects of beta cell function.-Genetic defects in insulin action.-Diseases of the exocrine pancreas as cystic fibrosis.-Endocrinopathies as Cushing’s syndrome.-Drug or chemical-induced as glucocorticoids.-Infections.-Uncommon forms of immune-mediated diabetes.

Impaired Glucose Tolerance) Impaired Fasting Glucose, Prediabetes) 

Blood glucose levels at borderline stage . Higher risk for macroangiopathy & cardiovascular mortality than normal person. 20-30% develop clinically overt DM within 10 years.

Therefore, need follow-up & weight reduction.

Diagnosis of Diabetes Mellitus
1-Fasting plasma glucose test 126 mg/dL and above is diagnostic 2-Oral glucose tolerance test (OGTT) 200 mg/dL and above is diagnostic 3- Hb A1c 6% and above is diagnostic


Fasting plasma glucose test
Measures plasma glucose after at least 8 hours without eating to detect diabetes or pre-diabetes
Diagnosis
Fasting Plasma Glucose Result (mg/dL)
Normal
70-99
Pre-diabetes(impaired fasting glucose)
100 to 125
Diabetes
126 and above

Oral glucose tolerance test (OGTT)

Measures plasma glucose after at least 8 hours without eating & 2 hours after drink a liquid containing 75 gm glucose. More precise in diagnose diabetes or especially pre-diabetes.

Gestational diabetes

Long-Term Complications of Diabetes Mellitus
1-Microangiopathy resulting in the development of retinopathy, nephropathy& neuropathy. 2-Macroangiopathy resulting in atherosclerosis and coronary heart disease.