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Metabolic Pathways Fall into Three Categories

  1. Anabolic pathway are those involved in the synthesis of compounds constituting body structure and machinery.
  2. Catabolic pathways involve oxidative processes that release free energy, usually in the form of high energy phosphate or reducing equivalents.
  3. Amphibolic pathways have more than one function and act as link between anabolic and catabolic pathway eg. the citric acid cycle.

Compartmentation of Major Pathway of Metabolism

  1. Cytosol.  Glycolysis, Pentose phosphate pathway, fatty acid synthesis
  2. Mitochondrial matrix. Citric acid cycle, Oxidative phosphorylation, β-oxidation of fatty acids, ketone body formation.
  3. Interplay of both compartments.  Gluconeogenesis, Urea synthesis

Body Stores of Metabolic Fuels

  1. Glucose circulating in the blood is a major metabolic fuel.
  2. Carbohydrate is stored primarily as glycogen in the liver and skeletal muscle.
  3. Triacylglycerol are stored primarily in the adipose tissue.
  4. Body protein also may be considered a source of fuel because amino acids may be converted to either glucose or ketone bodies.

Feeding-Fasting Cycle

  1. The fed (postprandial) state occurs during and just after a meal. Plasma substrate levels are elevated above fasting levels, and the metabolic fuels used by tissues may be derived directly from absorbed food molecules.
  2. The fasting (postabsorptive) state occurs several hours after eating. Metabolic fuels used by tissues are derived from mobilized stores of fuel molecules.
  3. Starvation occurs after extended fasting (i.e., 2 or 3 days without food).


Figure: Role of the respiratory chain of mitochondria in the conversion of food energy to ATP. Oxidation of the major foodstuffs leads to the generation of reducing equivalents (2H) that are collected by the respiratory chain for oxidation and coupled generation of ATP.

Non-Hormonal Regulations of Metabolic Pathways

  1. Allosteric control.  In certain pathways, the activity of a key enzyme that catalyzes the rate-limiting, committed step in the pathway is modulated by the levels of metabolites that act as activators or inhibitors.
    1. Glycolysis
      1. Phosphofructokinase is the site of regulation.
      2. Activators are fructose-2, 6-bisphoshate (F2, 6BP) and adenosine monophosphate (AMP).
      3. Inhibitors are citrate and adenosine triphosphate (ATP).
    2. Gluconeogenesis
      1. Fructose-1, 6-bisphosphatase (F1, 6BPase) is the site of regulation.
      2. Activators are citrate and ATP.
      3. Inhibitors are F2, 6BP and AMP.
    3. Acetyl coenzyme A (CoA) carboxylase is the site of regulation.
    4. The activator is citrate.
    5. The inhibitor is palmitoyl CoA.
    6. Fatty acid synthesis
  2. Respiratory control.  Under respiratory control, the flux through a pathway matches the need of the cell for ATP. Pathways regulated in this manner are:
    1. Citric acid cycle
    2. Fatty acid synthesis
    3. Oxidative phosphorylation
  3. Covalent modification.  Hormone-triggered reaction cascades, which result in the covalent modification of a key enzyme of a pathway, are used to regulate the following pathways:
    1. Glycogenesis.  Glycogen synthase is inactive when phosphorylated and active when dephosphorylated.
    2. Glycogenolysis. Glycogen phosphorylase is active when phosphorylated and inactive when dephosphorylated.
  4. Substrate availability.  Primarily determines the flux of metabolites through the following:
  1. Pentose phosphate pathway
  2. Urea cycle

Hormonal Regulation of Metabolic Pathways

Certain hormones exert direct and indirect effects that regulate the flow of metabolites through certain pathways.
  1. Insulin signals the fed state through the following actions.
    1. Insulin stimulates the synthesis of glycogen, fat, and proteins.
    2. Insulin inhibits the degradation of glycogen, fat, and proteins.
  2. Glucagon and epinephrine signal the fasting state through the following actions.
  3. Glucagon and epinephrine inhibit the synthesis of glycogen, fat, and proteins.
  4. Glucagon and epinephrine stimulate the degradation of glycogen, fat, and proteins.
  5. Epinephrine also signals stressful states when mobilization of fuel is required.

The Flow of Key Metabolic Intermediates between Different Pathways

  1. Glucose-6-phosphate may be converted to:
    1. Glucose in gluconeogenesis tissues.
    2. Glucose-1-phosphate and used in glycogen synthesis.
    3. Pyruvate via glycolysis.
    4. Ribose-5-phosphate, a substrate for nucleotide synthesis, via the pentose phosphate pathway.
  2. Pyruvate may be converted to:
    1. Oxaloacetate and metabolized via the citric acid cycle.
    2. Acetyl CoA by pyruvate dehydrogenase.
    3. Alanine via transamination.
    4. Lactate in muscle tissue and red blood cells by lactate dehydrogenase.
  3. Acetyl CoA may undergo any of the following:
    1. Oxidization to carbon dioxide (Co2) via the citric acid cycle.
    2. Usage in fatty acid synthesis
    3. Conversion to 3-hydroxy-3-methylglutaryl CoA (HMG CoA), which is a precursor of:
      1. Cholesterol            
      2. Ketone bodies
Key Junctions are– Glucose-6- Phosphate, pyruvate, Acetyl COA.


Effect of insulin on major metabolic pathway (effects of carbohydrate feeding)
Pathway Effect Regulated enzyme
Carbohydrate metabolism
Glycolysis ↑Phosphofructokinase-I,  ↑Pyruvate kinase,
↑Pyruvate dehydrogenase
Gluconeogenesis ↓Pyruvate carboxylase, ↓PEP carboxykinase, ↓fructose-1, 6-bisphophatase ↓glucose-6-phosphotase
Glycogenesis ↑glucokinase, ↑ glycogen synthase
Glycogenolysis ↓glycogen phosphorylase
Lipid metabolism
Lipogenesis ↑Acetyl-Co carboxylase, ↑Fatty acid synthase
Lipolysis ↓Hormone sensitive lipase
Cholesterol Synthesis ↑HMG-CoA reductase
Triacylglycerol Synthesis ↑Acyl-CoA-glycerol-3-phosphate transferase, ↑glycerol kinase
Lipoprotein degradation ↑Lipoprotein lipase
Protein metabolism
Protein synthesis ↑RNA polymerase and ribosome assembly
Note:- Pyruvate dehydrogenase is neither a glycolytic nor a TCA cycle enzyme, it acts as a bridge between the two.


Metabolic Profile of Specilized Tissues

A. Brain
  1. Glucose is virtually sole fuel of human brain, except during prolonged starvation it utilises ketone bodies.
    1. Brain lacks fuel stores hence requires continuous supply of glucose.
    2. Brain accounts for 60% of the utilization of the glucose by body in the resting state.
    3. Fatty acids can not serve as fuel for brain bound to albumin, they can not transverse blood brain barrier.
  1. Muscle.
    1. The major fuels for muscle are glucose, fatty acids and ketone bodies.
    2. Muscle differ from brain in having large store of glycogen which is readily converted into glucose 6- PO4 for use within muscle cells.
    3. Muscle like brain lacks Glucose-6- Phosphatase, so it does not export glucose.
    4. In actively contracting skeletal muscle, rate of glycolysis far exceeds that of citric acid cycle. Much of pyruvate formed is reduced to lactate which flows to liver and is converted to glucose, known as cori cycle.
    5. In resting muscle, fatty acids are the major fuel.
    6. Ketone bodies also serve as fuel for heart muscle.
  2. Adipose tissue
    1. Liver is major site of fatty acid biosynthesis whereas function of adipose tissue is to activate these fatty acids and to transfer the resulting CoA derivatives to glycerol.
    2. Glycerol-3- Phosphate, a key intermediate in biosynthesis comes from reduction of dihydroxyacetone phosphate formed during glycolytic pathway.
    3. Adipose tissues are unable to phosphorylate endogenous glycerol because they lack glycerol kinase. Hence, adipose cells need glucose for the synthesis of triacylglycerol.
    4. Triacylglycerol are hydrolyzed to fatty acids and glycerol by hormone sensitive lipases. If gycerol-3- Phosphate is abundant, many of fatty acid so formed is re-esterified to triacylglycerol. If glycerol-3- Phosphate is in short supply, FA are released in bloodstream.
      Adipose tissue.  The function of adipose tissue is to store and release fatty acids as needed for fuel.
      Thus, glucose level inside adipose cells is a major factor in determining whether fatty acids are released into the blood.
  3. Liver.  The metabolic activities of liver are essential for providing fuel to brain, muscle and other peripheral organs.
The liver plays a central role in metabolism in regulating the serum levels of glucose and other metabolic fuels.
  1. The liver is responsible for the maintenance of blood glucose levels.
  2. During the fed state, it takes up excess glucose for storage as glycogen or conversion to fatty acids.
  3. During the fasting state, glycogenolysis and gluconeogenesis by the liver are major sources of glucose for the rest of the body.
  4. The liver serves as the major site of fatty acid synthesis.
  5. The liver synthesizes ketone bodies during starvation.
  6. The liver synthesizes plasma lipoproteins.
Brain Glucose Glucose Ketone bodies
Heart Fatty acids Fatty acids Ketone bodies
Liver Glucose Fatty acids Amino acids
Muscles Glucose Fatty acids Fatty acids & ketone bodies
Adipose tissue Glucose Fatty acids Fatty acids & ketone bodies
RBCs Glucose Glucose  

Metabolic Adaptations in Starvation

  1. A typical well nourished man has fuel reserves of 1600 kcal in glycogen, 24,000 kcal in mobilizable protein and 1,35,000 kcal in triacylglycerol.
  2. Carbohydrate reserves are exhausted in only a day, because brain cannot tolerate lower glucose level for even short period.
    1. So, the first priority of metabolism in starvation is to provide sufficient glucose to brain and other tissues (such as red blood cells), that are absolutely dependent on glucose.
    2. Second priority of metabolism in starvation is to preserve protein. This is accomplished by shifting the fuel being used from glucose to fatty acid and ketone bodies.
  3. Metabolic changes during first day of starvation
    1. Low blood sugar level leads to decreased secretion of insulin and increased secretion of glucagon.
    2. Dominant metabolic processes are mobilization of triacylglycerol in adipose tissue and gluconeogenesis by the liver.
    3. The concentration of Acetyl CoA and citrate increase, which switch off glycolysis.
    4. The uptake of glucose by muscle is markedly diminished because of low insulin level whereas fatty acid enters freely. Therefore, muscle shifts almost entirely from glucose to fatty acid for fuel.
  4. After about third day of starvation large amounts of acetoacetate and β-hydroxybutyrate are formed by liver and about a third of the energy needs of the brain are met by ketene bodies. The heart also uses ketone bodies as fuel. The preferred ketone body by the brain is β-hydroxybutyrate.
  5. After several weeks of starvation, ketone bodies become the major fuel of the brain. Only 40 g. of glucose is needed per day for the brain, compared with 120 g. in the first day of starvation. Consequently the rate of muscle breakdown during prolonged starvation 25% of its rate after a several day fast.

The survival time in starvation therefore depends much more in the size of fat reserves than on muscle mass.

An Overview of Integration of Metabolism


Compartmentration Of Metabolic Pathways

Various metabolic processes occurs in different subcellular compartments (organelles). This compartmentation of pathways in separate subcellular compartments permits integration and regulation of metabolic pathways.

Site Cycle / Reactions
Cytosol Glycolysis (EMP Cycle), HMP shunt, fatty acid synthesis, glycogenesis, glycogenolysis, Bile acid / Salt synthesis, cholesterol synthesis
Mitochondria Kreb's cycle (citric acid cycle), Electron transport chain (ECT), Fatty acid oxidation, Ketogenesis
Both cytosol and mitochondria Gluconeogeesis, Urea cycle
Peroxisomes Oxidation of very long chain fatty acids
Smooth endoplasmic reticulum Triglyceride synthesis, Steroid synthesis, cholesterol synthesis, phospholipid synthesis
Rough endoplasmic reticulum (ribosomes) Protein synthesis
Nucleus DNA and RNA synthesis


Important Points To Remember 

  1. Vit. deficiency in pancreatic insufficiency: Vit. A
  2. Milling of rice cause loss of Thiamine (Vit. B2 & Protein also)
  3. Parboiling (Hot soaking) preserves above vitamins.
  4. Riboflavin deficiency is almost always associated with pyridoxine .deficiency.
  5. Mild hemolytic anemia is associated with vit E deficiency.
  6. Deficiency of Vit. E rarely occur in newborn.
  7. Co-enzyme A synthesis require Vit. B6 & Co-enzyme. A is active form of pantothenic Acid.
  8. Heat stable and light sensitive: Vit. K & B2 (Riboflavin)
  9. Heat labile vitamins Vit. C & Folic acid.
  10. Vit. A deficiency causes: Oro-oculo genital syndrome.
  11. Se-deficiency, Cobalt-excess & Fe-excess causes cardiomyopathy
  12. Mn Toxicity is associated with," Parkinsonism”
  13. Al deficiency is associated with," Alzheimer s disease“
  14. Cadmium - Ouch-Ouch disease
  15. Aresnic & Thallium," Black foot disease”
  16. Non-heme iron is present in foods of vegetable origin (Legumes, nuts, green leafy vegs, jaggery) Iron is in ferric (Fe+++) form.
  17. Foods rich in heme iron are liver, meat, poultry & fish (Iron is in ferrous (Fe++) form, better for absorption.
  18. All cytochromes are dehydrogenases except cytochrome oxidases.
  19. Large amounts of iron inhibitors are present in vegetarian foods - like phytate in bran, phosphate in egg yolk, tannin in tea and oxalates in vegetables.
Common clinical features of Micronutrient Deficiency
Zn   ------   Perioral pustular rash
Cu   ------   Microcytic anemia
Cr    ------   Hyperglycemia
Mn   ------   Dermatitis

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