2.2 carbohydrate metabolism part 2

8/11/2019 2.2 Carbohydrate Metabolism Part 2

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Biochemistry A: CARBOHYDRATE METABOLISM Part II

Dr. Remedios Santos Page 1of 13

26 Jul 2013 Section 1D-MD

GLUCONEOGENESIS

- Includes all pathways and mechanisms responsible for converting noncarbohydrates to glucose or glycogen.

- Not a simple reversible path of glycolysis due to the 3 irreversible steps.

- It is the reverse of 2 pathwaysinhibits glycolysis and Krebs, stimulates gluconeogenesis.

- Involves mitochondria (Krebs) and cytosol (glycolysis).

Importance of gluconeognesis:

1)

It meets the needs of the body for glucose when sufficient CHO is not available from the diet or glycogen reserves.

2) Glucose is also important in maintaining the level of intermediates of the Krebs cycle even when fatty acids are the

main source of acetyl CoA in the tissues.

3) Gluconeogenesis clears lactate produced by muscle and erythrocytes and glycerol produced by adipose tissues.

The two major organs involved in gluconeogenesis are the liver and kidneys.

Any metabolite that can be converted into pyruvate or citric acid cycle intermediate can serve as a precursor of glucose.

The major gluconeogenic precursors are:

1.

Lactate

2.

Glycerol

3. Glucogenic amino acids

4. Propionate (in ruminants)

The following irreversible reactions in glycolysis must be reversed in gluconeogenesis:

1. Phosphoenolpyruvate to pyruvate

- Pyruvate carboxylasereverses this reaction, converts pyruvate to oxaloacetate.

- Phosphoenolpyruvate carboxykinase(PEPCK) catalyzes the conversion of oxaloacetate to phosphoenolpyruvate.

2. Fructose-6 phosphate to fructose 1,6 bisphosphate

- Fructose 1,6-bisphosphatereverses this reaction. It is present in the liver, kidney, and striated muscle; absent in

heart muscle and smooth muscle.

- Activator of glycolysis, rate-limiting enzyme.

- Fructose 2,6-bisphosphateis the inhibitor of fructose 1,6-bisphosphate in the liver.

3.

Glucose to glucose-6 phosphate

- Glucose-6 phosphatasereverses this reaction. It is present in liver and kidney but absent from muscle and adipose

tissues. Its presence allows a tissue to add glucose to the blood.

Regulation of gluconeogenesis

1. Pyruvate carboxylase reactioninactive in the absence of acetyl CoA

2.

Fructose bisphosphate reactioninhibited by AMP

Glycolysis: hypoglycaemic pathway

Gluconeogenesis: hyperglycaemic pathway

Amino acids to ketoacidsDeamination (removal)/Transamination (transfer)

Each amino acid has a corresponding ketoacid.

Lactic acidosiscannot convert pyruvate to acetyl CoA, channelled towards lactic acid production

Pentosemia/Pentosuriawhen transketolation doesnt take place


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MAJOR PATHWAYS IN GLUCONEOGENESIS in the Liver

IRREVERSIBLE

ISOMERASE

IRREVERSIBLE

ENTRY PT. OF GLYCEROL

IRREVERSIBLE

ENTRY PT. OF LACTATE

NO ENZYME TO REPLACE,

MUST BE CONVERTED TO OXALOACETATE,

MALATE, BACK TO OXALOACETATE

NO TRANSPORT SYSTEM

SO CONVERT TO MALATE FIRST


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SUMMARY:

Increased ATP Glycolysis and Krebs cycle are inhibited

Increased acetyl CoA, citrate or NADH Gluconeogenesis is stimulated

Low Energy charge Glycolysis and Krebs are stimulatedRespiratory fuels not available Gluconeogenesis is inhibited

HEXOSE MONOPHOSPHATE SHUNT (HMP SHUNT)

-

Phosphoguloconate shunt; Pentose phosphate pathway, Warburg-Dickens pathway

- Locationcytosol

-

Rate-limiting enzyme: Glucose-6-phosphate dehydrogenase (G-6-P-D)

2 Major Functions of the HMP shunt

1. Generation of NADHPH for reductive synthesis fatty acid and steroid biosynthesis; reduction of glutathione

(detoxifying agent if reduced)

2.

Provision of ribose for nucleotide and nucleic acid biosynthesis

Other function: interconversion of sugars

THE HMP SHUNT:

RATE-LIMITING

1 mol

NON-OXIDATIVE STAGE: 1 mol

INTERCONVERSION OF SUGAR

TRANSFER 2 CARBONS, NEED THIAMINE TO ACTIVATE

TRANSFER 3 CARBONS


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HMP SHUNTCLINICAL ASPECT

- G-6-P-D Deficiency(Deficiency of glucose-6-phosphate dehydrogenase)

Wernicke-Korsakoff Syndrome:

- Thiamine not absorbed in alcoholics

-

No transketolase activation

- Low energyparalysis

- Severely impaired memory

The Pentose Phosphate Pathway is divided into:

1. Oxidative stage NADPH is produced as glucose-6-phosphate is converted to the five-carbon compound ribulose-6-

phosphate.

2. Non-oxidative stage This stage is a means for disposing of the pentose phosphate formed in the oxidative stage by

providing a route to glycolysis. In this stage, ribulose-5-phosphate is converted to fructose-6-phosphate and

glyceraldehydes-3-phosphate, intermediates of the glycolytic pathway. Both fructose-6-phosphate and

glyceraldehydes-3-phosphate can be metabolized further through either the glycolytic or gluconeogenic pathways.


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GLYCOGEN METABOLISM

GLYCOGENmajor storage form of carbohydrates in mammals

- the role of glycogen in mammals is to store glucose in times of plenty (after feeding) and to supply glucose in

times of need (during fasting or fight or flight situations)

-

The major tissues involved in the storage and use of glycogen are the liver and muscle. In muscle, glycogen is used as a store of readily available fuel for muscle contraction.

The glycogen stores in the liver are largely converted to glucose that exits liver cells and enters the

bloodstream to be transported to other tissues.

GLYCOGENESIS

-

refers to the intracellular synthesis of glycogen occurring chiefly in the liver and muscles

- precursor are glucose units

- requires a glycogen primer

- The glucose donor in the biosynthesis of glycogen is UDP-glucose, an activated form of glucose. By the action of the

enzyme glycogen synthase, the C-1 of the activated glucose of UDP-glucose forms a glycosidic bond with the C-4 of a

terminal glucose residue of glucogen, liberating uridine diphosphate (UDP). A pre-existing glycogen molecule, or

primer must be present to initiate this reaction.

- The addition of glucose residues to the glycogen primer occurs at the nonreducing, outer end of the molecule so that

the branches of the glycogen tree become elongated as successive 14 linkages are formed.

- When the chain has been lengthened to a minimum of 11 glucose residues, a second enzyme, the branching enzyme

(also called amylo [14] [16]transglucosidase) transfer a part of the 14 chain (minimum length of 6 glucose

residues) to a neighboring chain to form a 16 linkage, thus establishing a branch point in the molecule.

PATHWAY OF GLYCOGENESIS AND GLYCOGENOLYSIS IN THE LIVER


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ACTIVATION AND INACTIVATION OF LIVER PHOSPHORYLASE

GLYCOGENOLYSIS

GLYCOGENESIS

GLYCOGENESIS

GLYCOGENOLYSIS

GLYCOGENOLYSIS

- intracellular degradation of glycogen

-

The first step of glycogen degradation is catalyzed by the enzyme glycogen phosphorylase. This enzyme is specific for

the phosphorylytic breaking (phosphorolysis) of the 14 linkages of glycogen to yield glucose-6-phosphate. The

terminal glucosyl residues from the outermost chains of the glycogen molecule are removed sequentially until

approximately 4 glucose residues remain on either side of a 16 branch.

- Another enzyme, alpha-(14) (14) glucan transferase, transfers a trisaccharide unit from one branch to

another, exposing the 16 branch points.

-

The hydrolytic splitting of the 16 linkages requires the action of debranching enzyme (also called amylo (16)

glucosidase. With the removal of the branch, further action by phosphorylase can proceed.

REGULATION OF GLYCOGENESIS AND GLYCOGENOLYSIS

- cyclic AMP integrates the regulation of glycogenesis and glycogenolysis

- The principal enzymes controlling glycogen metabolism are glycogen phosphorylaseand glycogen synthase. They are

regulated by a complex series of reactions involving both allosteric mechanisms and covalent modifications due to

reversible phosphorylation and dephosphorylation of the enzyme protein.


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GLYCOGENESIS and GLYCOGENOLYSIS are opposing pathways!

GLYCOGENESIS GLYCOGENOLYSIS

Add sugar at the 1,4 UDPG

Minimum of 11 unitsyou can add a branch

5 units1 branch

Alternate addition of glucose at 1,4 through glycogen

synthase

Make branch using branching enzyme

Remove 1,4 phosphorylyze, use phosphorylase

Hyperglycemic: glycogenglucose

Cyclic AMP exerts two effects in inhibiting glycogen synthesis:

1.

Inactivation of glycogen synthase

2. Inhibition of phosphoprotein phosphatise, whose activity would tend to restore activity of glycogen synthase

Hormones affecting Glycogen synthesis and degradation

1.

Insulinactivates glycogen synthase so it promotes glycogenesis

2. Glucagon and epinephrineinhibits glycogen synthase by activating cyclic AMP thus inhibiting glycogenesis

GLYCOGEN STORAGE DISEASES


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THE URONIC ACID PATHWAY

- A pathway for the conversion of glucose to glucuronic acid, ascorbic acid and pentoses

- An alternative oxidative pathway for glucose but it does not lead to the generation of ATP

- The glucuronic acid formed serves as a precursor of ascorbic acid in those animals that synthesize vitamin C, but in

humans it is converted to L-Xylulose, the kentopentose excreted in Essential Pentosuria. Humans, other primates, and

the guinea pig lack the enzyme that converts L-gulono-lactonse to L-ascorbic acid and therefore must satisfy theirneeds for ascorbic acid by its ingestion. This enzyme is called L-gulonolactone oxidase.

-

The UDP-glucuronate formed is the active form of glucuronic acid for reactions involving incorporation of glucuronic

acid into proteoglycans or for reactions in which glucuronate is conjugated to such substrates as steroid hormones,

certain drugs, or bilirubin.

- Cannot synthesize Vit. C

URONIC ACID PATHWAY

IMPORTANT TO CONJUGATE

BILIRUBIN TO BE EXCRETED

WE DONT HAVE THIS. NOT STORED IN THE

BODY, WATER-SOLUBLE.

CONVERSION OF GALACTOSE TO GLUCOSE-

Galactose is readily converted to glucose in the liver. The ability of the liver to accomplish this conversion may be used

as a test of hepatic function in the galactose tolerance test. Galactose is needed in the body for the formation of

lactose as well as for the synthesis of glycolipids (cerebrosides), proteoglycans, and glycoproteins.

- Infants fed a normal milk diet rely on the pathway of galactose metabolism. In the most common and severe form of

the genetic order galactosemia (the inability to properly metabolize galactose), infants are usually deficient in

galactose-1-phosphate uridyl transferase. In such cases, galactose-1-phosphate accumulates in the cells and this can

compromise liver function leading to jaundice. The liver damage is potentially fatal. Other effects include damage to


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the central nervous system. Screening for galactose-1-phosphate uridyltransferase in the red blood cells of the

umbilical cord allows detection of galactosemia at birth, and the severe effects of this genetic deficiency can be

avoided by excluding lactose from the diet.

*In red boxescause 3 kinds of galactosemia. In the brain, can cause mental retardation. In the eyes, can cause opacity oflens (cataract).

CONVERSION OF FRUCTOSE TO GALACTOSE


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Fructose to Glucose:

Fructosehexokinase

Fructose 6 phosphateisomerase

Glucose 6 phosphateglucose 6 phosphatase

Glucose

SOURCES OF BLOOD GLUCOSE

1. From carbohydrates in the diet

2.

From the various glucogenic compounds that undergo gluconeogenesis (if beyond 24 hrs.) amino acids, lactate,glycerol (from fats, for several days)

3. From the liver glycogen thru glycogenolysis

CONTROL OF BLOOD GLUCOSE CONCENTRATION

1.

Role of the liver

- Liver glycogenolysis

- Gluconeogenesis

- Severe liver disease3 months before you die! Because if the liver is diseased, you cant metabolize any food.

Increased blood glucosedecreased glucose output by the liver

Decreased blood glucoseincreased output of glucose by the liver

2.

Role of Insulinonly hormone that lowers blood sugar

3. Insulin antagonistsall the rest of the hormones

PHYSIOLOGIC EFFECTS OF INSULIN

A.

EFFECTS ON CARBOHYDRATE METABOLISM

1. HYPOGLYCEMIC: Increases utilization of glucose by the cells

a. Effect on membrane transport glucose

- Insulin promotes mobilization of glucose transporters (mainly in the adipose tissues)

-

Insulin also facilitates simple diffusion (hepatic cells)without insulin!

b.

Insulin increases hepatic glycolysisstimulates glucokinase, PFK, pyruvate kinase. these are all controlenzymes of glycolysis.

2. HYPOGLYCEMIC: Insulin increases glycogenesis (liver and muscle) insulin inhibits cyclic AMP thereby activating

glycogen synthase

3. HYPERGLYCEMIC: Insulin inhibits glycogenolysisinhibits cyclic AMP thereby inactivating phosphorylase

4. HYPERGLYCEMIC: Insulin inhibits gluconeogenesis decreases amount of hepatic PEPCK by selectively inhibiting

transcription of the gene that codes for PEPCK mRNA

B. EFFECTS ON LIPID METABOLISM

1. Insulin stimulates lipogenesis in adipose tissues

2. Insulin inhibits lipolysis in liver and adipose tissues

C. EFFECTS ON PROTEIN METABOLISM

1. Stimulates protein synthesis

2. Stimulates uptake of amino acids into muscles

The simplest way to describe the actions of insulin is to say that it signals the fed state and thereby acts to promote...

1. Uptake of fuel substrates into some cells Glucose uptake into muscle and adipose tissue is controlled by insulin.

The uptake of glucose into the liver is independent of insulin.


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2. Storage of fuelslipids and glycogen

3.

Biosynthesis of macromoleculesnucleic acids and proteins

INSULIN ANTAGONISTS

1. GLUCAGON liver: glycogenolysis

-

Increases blood glucose by promoting liver glycogenolysis and increasing gluconeogenesis- Glucagon binds to cell membrane activates adenyl cyclise increases cAMPpromotes glycogenolysis in the

liver

- Glucagon has no effect on glycogenolysis in muscles

- Glucagon stimulates PEPCKincreased gluconeogenesis

-

Glucagon inhibits glycolysis by promoting phosphorylation of pyruvate kinase thereby inactivating it

- Primary target of glucagonLIVER

- Major signal for the release of glucagondecreased blood sugar level

2. EPINEPHRINE liver and muscle: glycogenolysis

- Catecholamines

-

Increases blood sugar level by:a. Increasing glycogenolysis, decreasing glycogenesissame mechanism as glucagon

b.

Increasing gluconeogenesis

c. Decreasing insulin release

d.

Increasing glucose uptake in muscles and other organs

3. GROWTH HORMONEpituitary gland! Increases blood sugar level by:

a. Increasing liver gluconeogenesis

b. Decreasing peripheral utilization of glucose by inhibiting glycolysis, inhibits glucose transport

4. CORTISOL (GLUCOCORTICOIDS)increases blood sugar level by:

a.

Increasing gluconeogenesis (increasing protein catabolism in the peripheral tissues)b. Decreasing glucose uptake and utilization by extrahepatic tissues

5. THYROID HORMONEincreases blood sugar level by increasing glucose absorption in the small intestines

DIABETES MELLITUS

Diagnosis:

a. FASTING BLOOD SUGAR (FBS)

> Normal Blood Sugar Level: 60-120 mg/dL> Fasting Blood Sugar taken 3 times for 3 days in a row

> Fasting for 8-10 hours before the test is needed. Do not over fast to avoid discrepanciespatients can

manipulate so we dont usually rely on this test for the diagnosis!

> Consistent above normal findings for 3 consecutive reading is indicative of Diabetes Mellitus

> May be performed together with glycosylated haemoglobin (but this test is very expensive)

***GLYCOSYLATED HEMOGLOBIN

- not affected by fasting


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- gives the patients blood sugar for the past 2-3 months

- if it gives a high result, it is indicative of DM even if FBS reading is normal

b. ORAL GLUCOSE TOLERANCE TEST

> Measure FBS first, then give the prepared glucose syrup

> More reliable than FBS> Blood extraction done 5 times to test for blood glucose testing

> Glucose Toleranceis the ability to utilize glucose

3 PARTS OF GLUCOSE TOLERANCE TEST CURVE (GTT CURVE)

a. Normal Fasting Blood Sugar Level

b. 30 minutes1 hour

- Blood Sugar Level increases and reaches its peak

- Temporary State of Hyperglycemia

- due to the absorption of glucose

c. 2 hours

- Blood Sugar Level goes down

- it may overshoot causing blood sugar level to

decrease more than the original level

- Temporary State of Hypoglycemia

- due to action of insulin

PROLONGED GTT CURVE

- Present in Diabetes Mellitus

- It starts with a high FBS level, the elevation is long, and does not go down to normal in 2 hours time

FLAT GTT CURVE

- GTT curve neither increases nor decreases

- Failure to absorb glucose

- Present in cases of malabsorption

INVERTED CURVE

- a reverse curve

- blood sugar decreases further upon intake of glucose

- Present in patients with Insulinoma (tumor producong a lot of insulin) manifested by hyperinsulinemia

TYPES OF DIABETES

1. TYPE 1

- Insulin-dependent diabetes mellitus

- Youth onset

- Pancreas is totally not producing insulin

- complications set in at a young age. E.g. Diabetic Ketoacidosis

- Treatment: Insulin administration


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2. TYPE 2

- Non insulin-dependent diabetes mellitus

- Maturity Onset

- usually develops 40 y/o and above

- pancreas produces insufficient amount of insulin- Treatment: Drugs that helps the pancreas produce more insulin. You dont give insulin yet unless the patient is

not responding to 3 types of drugs

e.g. Sulfonylureas, Biguanides

3. TYPE 3

- Youth Onset Type 2

- Non insulin dependent but occurs in young age

- Insulin is normal, abnormal receptors

- also known as insulin resistance

- Regular exercise stimulates production of receptors. Best exercise: brisk walking 1 hour everyday!

- Treatment: Drugs to stimulate the formation of more receptors (more expensive than sulfonyl ureas)e.g. Glitazones

4. TYPE 4

- Endocrine type of diabetes

- Normal Insulin, normal receptor, normal pancreas, but blood sugar is extremely high (400-500)

- present in patients with pituitary tumor

- increase in production of all trophic hormones that includes:

> growth hormones

> adrenocorticotropic hormones - stimulates adrenal glands to produce glucocorticoids

> thyroid stimulating hormone -increases thyroid hormone synthesis

- Manifestation: suddenly cannot recognize the people around him because of the tumor. You do an open -closesurgery when the tumor has metastasized.

6. TYPE 5

- GLUCAGON RESISTANCE DIABETES

- Glucagon is normally stimulated when blood sugar goes down and it stops when blood sugar is normal

- in glucagon resistance, even if blood sugar is already high, it does not stop its activity making blood sugar level

increase further

- Treatment: Drugs that suppress glucagon effect

REMEMBER:The anti-diabetes drugs of one person may not be effective to another. Find out the cause of the diabetes

first!

2.2 carbohydrate metabolism part 2

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