Digestion is the the breakdown of food into small molecules. Digestion entails the physical grinding, softening, and mixing of food, as well as enzyme-catalysed hydrolysis of carbohydrates, proteins, and fats.

Digestion begins in the mouth, continues in the stomach, and concludes in the small intestine.

The products of digestion are mostly small molecules that are absorbed from the intestinal tract. Nutrients are absorbed through millions of tiny projections (the villi) in the intestinal lining and transferred into the bloodstream.

The bloodstream transports these small molecules into target cells, where they may be broken down completely to release energy as their carbon atoms are converted to carbon dioxide.

Others are excreted, and some are used as building blocks to synthesize new biomolecules.

Through a series of metabolic oxidations, the energy stored in glucose is converted to ATP energy and used to power other reactions within the cell.

• The initial metabolic fate of glucose is conversion into pyruvate and then usually to acetyl-CoA, the common intermediate in the catabolism of all foods.

• Acetyl-CoA delivers acetyl groups to the citric acid cycle for oxidation, with the energy captured transferred through the electron transport system, resulting ultimately in the formation of ATP.

• Glycolysis is the first of two sequential, catabolic pathways leading to ATP synthesis as a result of electron transfer. When glucose enters a cell from the bloodstream, it is immediately converted to glucose 6-phosphate.

• Once phosphorylated, glucose is trapped within the cell because phosphorylated molecules cannot cross the cell membrane unaided by a transporter.

  • Like the first step in many metabolic pathways, the formation of glucose 6-phosphate is highly exergonic and not reversible in the glycolytic pathway, thereby committing the initial substrate to the subsequent reactions.

    • Several pathways are available to glucose 6-phosphate.

  • When energy is needed, glucose 6-phosphate moves down the central catabolic pathway proceeding via the reactions of glycolysis to pyruvate and then to acetyl-CoA, which enters the citric acid cycle.

  • When cells are well supplied with glucose, excess glucose is converted to other forms for storage: into glycogen, the glucose storage polymer, by the glycogenesis pathway, or into fatty acids by entrance of acetyl-CoA into the pathways of lipid metabolism rather than the citric acid cycle.

  • Glucose 6-phosphate can also enter the pentose phosphate pathway. This multistep pathway yields two products important to our metabolism.

    • One is a supply of the coenzyme nicotinamide adenine dinucleotide phosphate (NADPH), a reducing agent that is essential for many biochemical reactions.

  • The other is ribose 5-phosphate, which is the precursor for the synthesis of nucleic acids (deoxyribonucleic acid [DNA] and ribonucleic acid [RNA]).

    • Glucose 6-phosphate enters the pentose phosphate pathway when a cell’s need for NADPH or ribose 5-phosphate exceeds its need for ATP.

Glycolysis is a series of 10 enzyme-catalysed reactions that converts a glucose molecule into two pyruvate molecules and in the process yields two ATP molecules and two NADH molecules.

Energy Investment Steps in Glycolysis:

• STEP 1: Phosphorylation :Glucose is carried in the bloodstream to cells, where it is transported across the cell membrane into the cytosol.

• STEP 2: Isomerization: The enzyme glucose 6-phosphate isomerase converts glucose 6-phosphate (an aldohexose) to fructose 6-phosphate (a ketohexose).

  • This conversion of a six-membered glucose ring to a five-membered ring with a ¬CH2OH group prepares the molecule for addition of another phosphoryl group in the next step.

• STEP 3: Phosphorylation :A second energy investment is made as phosphofructokinase converts fructose 6-phosphate to fructose 1,6-bisphosphate by reaction with ATP in an exergonic reaction.

  • This irreversible reaction is another major control point for glycolysis. When the cell is short of energy, adenosine diphosphate (ADP) and adenosine monophosphate (AMP) concentrations build up and activate the step 3 enzyme, phosphofructokinase.

  • When energy is in good supply, ATP and citrate build up and allosterically inhibit this enzyme. The outcome of steps 1–3 is the formation of a molecule ready to be split into the two 3-carbon intermediates that will ultimately become two molecules of pyruvate.

• STEP 4: Cleavage: Aldolase catalyses cleavage of the bond between carbons 3 and 4 in fructose 1,6-bisphosphate.

  • The products of this reversible reaction are dihydroxyacetone phosphate and glyceraldehyde 3-phosphate.

  • Only glyceraldehyde 3-phosphate can be used to generate energy, but these two 3-carbon sugar phosphates are interconvertible in an aldose–ketose equilibrium.

• STEP 5: Isomerization: Triose phosphate isomerase catalyses the conversion of dihydroxyacetone phosphate to glyceraldehyde 3-phosphate.

  • As glyceraldehyde 3-phosphate reacts in step 6, the equilibrium of step 5 shifts to the right.

  • The overall result of steps 4 and 5 is therefore the production of two molecules of glyceraldehyde 3-phosphate.

• STEP 6: Oxidation: Glyceraldehyde 3-phosphate from both steps 4 and 5 is oxidized to 1,3-bisphosphoglycerate by glyceraldehyde 3-phosphate dehydrogenase.

  • The enzyme cofactor NAD+ is the oxidizing agent for this reaction. Some of the energy from the exergonic oxidation is captured in NADH, and some is used in forming the phosphate.

  • This is the first energy-generating step of glycolysis.

• STEP 7: Phosphorylation :Phosphoglycerate kinase transfers a phosphate group from 1,3-bisphosphoglycerate to ADP.

  • The products of the reaction are 3-phosphoglycerate and ATP, the first ATP generated by glycolysis.

  • Because this step occurs twice for each glucose molecule, the ATP-energy balance sheet in glycolysis is even after step 7.

  • Two ATP molecules were spent in steps 1–5, and now they have been replaced.

• STEP 8: Isomerization: Phosphoglycerate mutase catalyses the isomerization of 3-phosphoglycerate to 2-phosphoglycerate. This rearrangement is necessary for the next step.

• STEP 9: Dehydration: Enolase catalyses the dehydration of 2-phosphoglycerate to phosphoenolpyruvate, the second energy-providing phosphate of glycolysis.

  • Water is the other product of this reaction.

• STEP 10: Phosphate :Transfer Pyruvate kinase transfers a phosphate group from phosphoenolpyruvate to ADP forming pyruvate and ATP in a highly exergonic, irreversible reaction.

  • The production of ATP by transfer of a phosphate group to ADP from another molecule is called substrate-level phosphorylation.

The conversion of glucose to pyruvate is a central metabolic pathway in most living systems. The further reactions of pyruvate, however, depend on metabolic conditions and the organism.

• Under normal oxygen-rich (aerobic) conditions, pyruvate is converted to acetyl-CoA in mammals. This pathway, however, is short-circuited in some tissues, especially when there is not enough oxygen present (anaerobic conditions).

• Under anaerobic conditions, pyruvate is instead reduced to lactate. When sufficient oxygen again becomes available, lactate is recycled back to pyruvate in muscle cells or to glucose via the Cori cycle in liver cells.

• A third pathway for pyruvate is conversion back to glucose by gluconeogenesis, which also occurs only in liver cells.

• This pathway is essential when the body is starved for glucose. The pyruvate necessary for gluconeogenesis may come not only from glycolysis but also from amino acids or glycerol from lipids.

• Use of protein and lipid for glucose synthesis occurs when energy needed exceeds energy intake, as in starvation, certain diseases, and some carbohydrate-restricted diets.

• Yeast is an organism with a different pathway for pyruvate; it converts pyruvate to ethanol under anaerobic conditions.

For aerobic oxidation to proceed, pyruvate first moves across the outer mitochondrial membrane from the cytosol where it was produced. Next, a transporter protein carries pyruvate across the otherwise impenetrable inner mitochondrial membrane.

Once within the mitochondrial matrix, pyruvate encounters the pyruvate dehydrogenase, a large multienzyme complex that catalyses the conversion of pyruvate to acetyl-CoA, the substrate for the citric acid cycle. The other product of the reaction, CO2 is exhaled.

Under aerobic conditions, NADH is continually re-oxidized to NAD+ during electron transport under anaerobic conditions, electron transport slows and so does the production of NAD+.

• The reduction of pyruvate to lactate results in the oxidation of NADH to NAD+, allowing glycolysis to continue. Lactate is oxidized to pyruvate by another pathway when oxygen is available.

Microorganisms often must survive in the absence of oxygen and thus have evolved numerous anaerobic strategies for energy production, generally known as fermentation.

• When pyruvate undergoes fermentation by yeast, it is converted into ethanol plus carbon dioxide. This process, known as alcoholic fermentation, is used to produce beer, wine, and other alcoholic beverages and also to make bread.

A stable blood glucose concentration is vital for proper functioning of the body. Wide fluctuations in glucose levels lead to unwanted side effects. The body uses the hormones insulin and glucagon to control blood glucose levels along with mechanisms to store and release glucose as needed.

Hypoglycemia occurs when there is lower than normal blood glucose concentration.

Hyperglycemia occurs when there is higher than normal blood glucose concentration.

Epinephrine accelerates the breakdown of glycogen, but primarily in muscle tissue, where glucose is used to generate energy needed for quick action.

Fats are our largest energy reserve, but adjusting to dependence on fat for energy takes several days because there is no direct pathway for generating glucose from the fatty acids in fats.

Catabolism of fatty acids to acetyl-CoA, oxidation of acetyl-CoA via the citric acid cycle, and production of ATP energy from electron transport is the path for generating energy from fat. Protein is also broken down into amino acids that can be used to generate energy.

Amino acids can enter the citric acid cycle for oxidation to energy or can be used to synthesize glucose in liver cells via the gluconeogenesis pathway.

Glycogenesis is the biochemical pathway for synthesis of glycogen, a branched polymer of glucose.

It occurs when glucose concentrations are high. It begins with glucose 6-phosphate and occurs via the three steps.

• Step 1: Phosphoglucomutase isomerizes glucose 6-phosphate to glucose 1-phosphate.

• Step 2: Pyrophosphorylase attaches glucose 1-phosphate to uridine triphosphate (UTP) producing uridine diphosphate (UDP)-glucose in a reaction driven by the release of inorganic pyrophosphate. UTP is a high energy compound similar to ATP. UDP serves as a carrier for glucose.

• Step 3: Glycogen synthase adds UDP-glucose to a glycogen chain, lengthening the chain by one glucose unit and freeing UDP in the process.

Glycogenolysis is the biochemical pathway for breakdown of glycogen to free glucose.

It occurs in the two steps. In muscle cells, this occurs when there is an immediate need for energy, while in liver cells, it occurs when blood glucose is low.

• Step 1: Glycogen phosphorylase simultaneously hydrolyzes a-1, 4 glycosidic bonds and sequentially phosphorylates glucose units. The product is glucose 1-phosphate.

• Step 2a: Phosphoglucomutase isomerizes glucose 6-phosphate to glucose 1-phosphate. In muscle cells, glucose 1-phosphate immediately enters glycolysis at step 2. This is the reverse of the same reaction in glycogenesis.

• Step 2b: In liver cells, glucose 6-phosphatase hydrolyzes glucose 6-phosphate to glucose that moves out of the liver to blood stream to raise blood sugar levels.

The Cori cycle converts lactate into pyruvate, the substrate for gluconeogenesis, a pathway that makes glucose from non-carbohydrate molecules (lactate, amino acids, and glycerol) beginning with pyruvate. This pathway becomes critical when glucose is not available.

Cori Cycle:

Lactate is a normal product of glycolysis in red blood cells and in muscle cells during vigorous exercise. The bloodstream moves lactate from muscle cells to liver cells; it is oxidized to pyruvate by lactate dehydrogenase.

• Pyruvate is the substrate for an 11-step series of reactions in the gluconeogenesis pathway; the final product is glucose, which is exported to tissues dependent on glucose but lack the gluconeogenesis pathway. The Cori cycle is essentially a recycling pathway.

Gluconeogenesis:

• Gluconeogenesis, the synthesis of glucose from noncarbohydrate sources, runs when available glucose from the diet and stored glycogen has been used up.

• Glucose is the preferred energy source for brain and blood cells and must be supplied.

• Although some of the steps in gluconeogenesis are the reverse of the identical step in glycolysis, the energy requiring steps in gluconeogenesis use different enzymes than the same steps in glycolysis and vice versa.

• The steps in gluconeogenesis are:

• Step 1: In an energetically expensive step, pyruvate carboxylase adds CO2 to pyruvate forming oxaloacetate. ATP is changed to ADP in this step.

• Step 2: In a second energetically expensive step, phosphoenolpyruvate carboxylase removes CO2 from oxaloacetate while adding a phosphate group from guanosine triphosphate (GTP) (similar to ATP) producing phosphoenolpyruvate and guanosine diphosphate (GDP).

• Steps 3–8: In reversible reactions, the same set of enzymes as found in glycolysis steps 4–9 convert phosphoenolpyruvate to fructose 1,6-bisphosphate via the same intermediates found in glycolysis.

• Step 9: In a one-way reaction, fructose 1,6-bisphosphatase hydrolyzes fructose 1,6-bisphosphate to fructose 6-phosphate.

• Step 10: In a one-way reaction, phosphohexose isomerase changes fructose 6-phosphate into glucose 6-phosphate.

• Step 11: In a one-way reaction, glucose 6-phosphatase hydrolyzes glucose 6-phosphate to glucose.