Integration, Specialization, and Regulation of Metabolism OF METAB… · and Regulation of...

Integration, Specialization,

and Regulation of Metabolism

Principles of Biochemistry (BCH 3000)

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Overall Strategies of Metabolism

1. Glycolysis

Degradation of glucose into two molecules ofpyruvate, ATP and NADH, respectively.

2. Gluconeogenesis

Precursors containing 3C (pyruvate, lactate,glycerol and some amino acids) are used to makeglucose, which occur in liver.

3. Pentose phosphate pathway

Glucose oxidized to ribose-5-phosphate withproduction of NADPH.

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4. -oxidation and fatty acid synthesis

Triacylglycerols are degraded to acetyl-CoA with generation of abundant NADH and FADH2 in mitochondria of skeletal muscle, heart and adipose tissue

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5. Amino acid degradation and synthesis

Amino acids that are not needed for protein synthesis or for specialized metabolism are degraded into fuel metabolism.

Amino acids converts to -keto acids by transamination process are then degraded by the citric acid cycle through several entry points (pyruvate, acetyl-CoA, -ketoglutarate, succinyl-CoA, fumarate and oxaloacetate)

Amino groups are collected in a form of glutamate will later transformed into urea by the urea cycle for elimination.

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6. Citric acid cycle

The central cycle collects acetyl-CoA from the degradation of carbohydrates, -oxidation of fatty acids and oxidation of some amino acids.

Required eight enzyme steps oxidizes acetyl-CoA to CO2 and H2O.

Each acetyl-CoA generates three NADH, one FADH2 and one ATP.

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7. Oxidative phosphorylation

Occur in mitochondria, which comprises of two activities:

• Electron transport from NADH and FADH2 to oxygen

• Phosphorylation of ADP to generate ATP

Allows for the recycling of the redox cofactors (NADH/NAD+; FADH2/FAD) and produces much ATP for energy

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1. Glucose-6-phosphate

Major metabolic junction for carbohydrate metabolism, especially in the liver.

Links the pathways of glycolysis, glycogen metabolism and the specialized pentose phosphate pathway.

2. Pyruvate

Links anaerobic carbohydrate metabolism (glycolysis) with aerobic metabolism (pyruvate dehydrogenase complex and citric acid cycle).

Used also in muscle lactate and gluconeogenesis.

Intermediates That Connect Pathways

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3. Acetyl-CoA

Main product from stage II metabolism of all three types of fuel molecules (carbohydrates, fatty acids and some amino acids).

It is further degraded to CO2 and H2O by entry into citric acid cycle

Also starting point for fatty acid and steroid synthesis

Excess production may be shunted toward the production of ketone bodies


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4. Oxaloacetate

Links amino acid metabolism to glucose metabolism and to pyruvate metabolism.


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Metabolic Integration and Specialization

Brain

Consumes 100-200 g of glucose/ day to produce ATP that essential to maintain membrane potentials for nerve impulse transmission (Na+-K+

ATPase pump).

Uses 15-20% of total oxygen in the body.

Brain cells do not store glycogen, thus constant supply of glucose from the bloodstream is needed.

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Skeletal muscle

Use glucose, fatty acids and some amino acids for fuel.

Energy demand is varied due to the level of activity.

Muscle cells can store glucose in the form of glycogen.


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Heart muscle

Need energy level less than skeletal muscle, but it stores little or no glycogen

Relies on arerobic metabolism of fatty acids for energy during resting state, but turn to glucose, lactate, pyruvate or ketone bodies on higher demand.

Liver

Catabolize and synthesize fatty acids, glucose, amino acids and ketone bodies for distribution via bloodstream to other tissue.

Control the level of blood glucose through the action of glucokinase.

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Adipose tissue (fat cells or adipocytes)

Important organ for long-term storage of fuel molecules.

Place for the synthesis and degradation of triacylglycerols.

Release stored fatty acids by hydrolysis, which catalyzed by hormone-sensitive lipase

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Production and Distribution of Ketone Bodies

Under conditions of fasting, starvation, untreated diabetes mellitus or a low-carbohydrate diet, acetyl-CoA is produced in abnormally large amounts due to excessive breakdown of fatty acids.

• It was due to the lack or impaired utilization of glucose.

Oxaloacetate levels will be reduced because the molecule is being drained from the citric acid cycle to make glucose.

Excess acetyl-CoA is diverted to the formation of ketone bodies.

Occurs mainly in the liver, but the products are distributed throughout the body via the blood

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Ketone Bodies formation

• Step 1 :

Two acetyl-CoA catalyzed by -ketothiolase produced Acetoacetyl-CoA

• Step 2 :

Acetoacetyl-CoA combines with another acetyl-CoA in a reaction promoted by HMG-CoA synthase producing HMG-CoA

• Step 3 :

HMG-CoA is cleaved by HMG-CoA lyase to acetoacetate and acetyl-CoA

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Ketone Bodies formation

Step 4 :

Acetoacetate will then under go two reactions

• (i) decarboxylation to acetone

• (ii) reduction to 3-hydroxybutyrate

Acetone

Volatile compound, expelled from the body during breathing and often can be detected on the breath of fasting individuals or of patients with untreated diabetes

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Hormones

Signaling molecules synthesized and secreted by endocrine glands and transported to their site of action via bloodstream

Metabolic Control by Hormones

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• Insulin

Synthesized in the beta cells of the pancreas and secreted into the bloodstream in response to increased levels of blood glucose

Increase the permeability of muscle and adipose cells to glucose uptake

Stimulate glycogen synthesis and glycolysis in the liver

Inhibit triacyglycerol hydrolysis in adipocytes

Stimulate triacylglycerol synthesis in the liver and adipose tissue

Increased the pyruvate dehydrogenase complex activity

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• Glucagon

Synthesized and secreted by alpha cells of the islet of Langerhans in the pancreas

Functions to increase blood glucose levels

Stimulates cells to enhance glycogen breakdown (through glycogen phosphorylase) and release glucose into the bloodstream

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• Epinephrine (Adrenaline)

Catecholamine that functions in the regulation of carbohydrate and fatty acid metabolism

Released from the adrenal medulla in response to metabolic stress

Provide elevated levels of glucose and fatty acids for energy metabolism

Induced when insulin secretion is inhibited and glucagon secretion is stimulated

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• The following sequence of events occur after carbohydrate-containing meal:

Blood glucose levels begin to rise

Increased in blood glucose, stimulates secretion of insulin and suppression of glucagon

Fatty acid synthesis is stimulated in the liver with enhanced storage of triacylglycerols

Abundant glucose available in muscle is stored in glycogen

Metabolic Responses in Conventional Lifestyle

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Metabolic Responses in Conventional Lifestyle

A few hours after meal, blood glucose levels begin to fall and the following events occur:

Insulin secretion is decreased and glucagon secretion increases

Glycogen is mobilized in the liver (activation of glycogen phosphorylase and inhibition of glycogen synthase)

Lipase action in adipocytes is activated by removal of insulin inhibition (increased fatty acids)

Decreasing levels of insulin slow glycolysis in muscle, liver and adipocytes by reducing their permeability to glucose

Glucose produced in liver (by gluconeogenesis) is transported to brain

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Metabolic Responses to Stressful Conditions

• Some examples of the disturbances are

1. fasting (starvation)

2. Dieting

3. exercising (sprinting or running a marathon) and

4. diseases (diabetes)

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• Starvation or Fasting

The stores of triacylglycerols in an average human last for 1-2 months. Degradation of fatty acids generates increased quantities of acetyl-CoA, thereby triggering production of ketone bodies.

The total muscle and liver glycogen last for only 12-18 hours. Some tissues such as muscle, heart and liver begin using fatty acids for fuel when glycogen and glucose levels decline.

Muscle protein appears as a source of abundant energy. Extensive muscle protein degradation can lead to loss of important enzymes and wasting of muscle tissue.

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• Dieting

Body will also experience the above sequence ofevents

Diabetes mellitus


Sixth leading cause of death in US

Characterized by abnormally high concentrations of glucose in the blood

Type I diabetes (insulin-dependent)

Due to inadequate secretion of insulin by the islet of Langerhans in the pancreas

Treatment by regular administration of insulin

Diabetes mellitus


Type II diabetes (insulin-resistant)

Insulin is produced normally, but the hormone function is less effective due to shortage of insulin receptors in cells

Current drugs used are Avandia and Starlix –enhance body’s use of insulin

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Biochemical Factors in Obesity

Obesity

The accumulation of excessive triacylglydcerols(fats) in adipocytes

Body weight more than 20% over an ideal standard weight

Major risk factor for diabetes, heart disease, high blood pressure, stroke and some cancers

Weight-regulating hormones regulates body weight, body temperature and other functions

They are transported via blood to the brain where they act on neurons in the hypothalamus and area that regulates the body

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Biochemical Factors in Obesity

Obesity

There are two neurons respond to the molecular signals by stimulating or inhibiting metabolic pathways that balance food intake and energy expenditure

NPY/AgRP – producing neurons that release neuropeptide Y (NPY), the protein that stimulates eating behavior

Melanocortin – producing neurons who products inhibit eating behavior. It is blocked by agouti-related peptide (AgRP)

Category BMI range - kg/m2

Severely underweight less than 16.5

Underweight from 16.5 to 18.5

Normal from 18.5 to 25

Overweight from 25 to 30

Obese Class I from 30 to 35

Obese Class II from 35 to 40

Obese Class III above 40

BMI = weight (kg)

height2 (m2)

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Hormones That Control Appetite

o Short-term regulator, ghrelin (appetite-stimulating hormone)

A peptide with 28 amino acids, produced in stomach

At maximum concentration in the blood when stomach is empty and drop rapidly after the meal

o Intermediate-term regulatory, PYY3-36 (appetite-inhibiting hormone)

A peptide hormone with 34 amino acids, produced in endocrine cells in the lining of the small intestines and colon

At maximum concentration after meal and remains high for several hours

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o Long-term regulators, insulin and leptin

Inhibit eating and enhance the breakdown of fuels for energy metabolism

Insulin is a major regulator of carbohydrate metabolism

Leptin a protein, act as a hormone to regulate body weight by monitoring the amount of fat stored in the body

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o Leptin

In humans, leptin levels increase with the percentage of body fat.

Researchers have discovered a direct correlation between human leptin levels and the body mass index (BMI).

It appears that obesity in humans is not the result of defective leptin or insufficient levels of leptin, but due to malfunction of the leptin signaling mechanism.

Other hormones like serotonin and neuropeptideY may be involved in leptin control.

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