Cellular metabolism

Amino acids can be used as building blocks for many other molecules, such as neurotransmitters, hormones, or heme groups. Some can also serve as substrates for the Kreb's cycle, gluconeogenesis, ketogenesis, or synthesizing other amino acids.

Out of the 20 amino acids, 9 are essential and must be obtained from the diet.

The key metabolic pathways in liver metabolism include:

1. Glycogenesis - Conversion of glucose to glycogen.
2. Glycogenolysis - Breakdown of glycogen to glucose.
3. Glycolysis - Conversion of glucose to pyruvate.
4. Gluconeogenesis - Formation of glucose from non-carbohydrate sources.
5. Lipogenesis - Synthesis of fatty acids from acetyl CoA.
6. Lipolysis/β-oxidation - Breakdown of triglycerides into fatty acids and glycerol.
7. Ketogenesis - Formation of ketone bodies from fatty acids.
8. Ketone oxidation - Utilization of ketone bodies for energy.
9. Krebs' cycle - Central metabolic pathway for energy production.
10. Electron transport chain - Final stage of cellular respiration, producing water from protons, oxygen, and electrons.

BMI is calculated using the formula: BMI = weight (kg) / height² (m²).

Obesity is associated with increased risks of:

• Heart disease
• Stroke
• Diabetes
• Many cancers

The risk of developing obesity is influenced by a combination of:

• Genetics
• Environment
• Caloric intake
• Hormonal influences

Inborn errors of metabolism are genetic disorders characterized by mutations that impair the processing of biomolecules, including disorders of carbohydrates, amino acids, or organic acids, and lysosomal storage diseases.

Many inborn errors of metabolism are identified through Newborn Screening, which screens for single gene defects that prevent enzymes from acting on their substrates.

The main anaerobic metabolic pathways in the cytosol include:

1. Glycolysis: Converts glucose into 2 ATP, 2 NADH, and 2 pyruvate through a 10-step pathway, regulated at steps 1, 3, and 10.
2. Fermentation: Transfers electrons from NADH to pyruvate to regenerate NAD+ when oxygen is absent.
3. Gluconeogenesis: An anabolic process that produces glucose from 3C substrates in the liver, reversing glycolysis with new enzymes at steps 1, 3, and 10.
4. Glycogenesis: Converts glucose-1-phosphate from glucose-6-phosphate into glycogen, catalyzed by glycogen synthase, occurring in a fed state.
5. Glycogenolysis: Breaks down glycogen to release glucose as glucose-1-phosphate, which can become glucose-6-phosphate for gluconeogenesis or glycolysis, occurring in an unfed state.

The Pentose Phosphate Pathway serves several important functions:

• Produces NADPH, which is essential for anabolic reactions, including fatty acid synthesis.
• Generates carbon intermediates that can be used for nucleotide synthesis.
• Allows for the regeneration of glycolysis intermediates (like fructose-6-phosphate and glyceraldehyde-3-phosphate) for energy production.

GLUT transporters facilitate the entry of glucose into the cell through passive transport, utilizing the concentration gradient.

Glycogenesis and glycogenolysis are two opposing processes:

Protein anabolism and catabolism are crucial for maintaining metabolic balance:

• Protein Anabolism: Occurs during the fed or post-prandial state, where amino acids are used to synthesize proteins, supporting growth and repair.
• Protein Catabolism: Takes place in the unfed state, where proteins are broken down through deamination in the liver to provide energy or substrates for gluconeogenesis.

The Smooth ER is involved in lipogenesis, which is the process of building triglycerides from glycerol and 3 fatty acids. These triglycerides are then packaged into lipoproteins such as LDL and HDL for transport in the body.

The main stages of aerobic metabolism in the mitochondria include:

1. Pyruvate oxidation/decarboxylation (Prep Stage): A redox reaction catalyzed by the Pyruvate Dehydrogenase Complex (PDC).
2. Kreb's cycle (Citric Acid Cycle): Involves redox reactions that produce ATP and many electron carriers such as NADH and FADH2.

β-oxidation is the process of breaking down fatty acids into acetyl CoA, FADH2, and NADH. This process occurs during the unfed state when the body needs to utilize fat stores for energy.

Ketogenesis is an anabolic process that builds ketones, which serve as an alternative fuel source derived from glucose. This process occurs during the unfed state when glucose availability is low, allowing the body to utilize fat as an energy source.

Metabolism consists of anabolic and catabolic reactions:

• Anabolic reactions: Synthesize complex molecules from simpler ones, requiring energy (endergonic).
• Catabolic reactions: Break down complex molecules into simpler ones, releasing energy (exergonic).

The stages of glucose catabolism include:

1. Glycogen degradation (glycogenolysis) and glucose transport into cells via GLUT transporters.
2. Glycolysis: Anaerobic breakdown of glucose in the cytosol.
3. Kreb's cycle and Electron Transport Chain: Aerobic processes occurring in the mitochondria or cell membrane of aerobic bacteria.

ATP (adenosine triphosphate) serves as the most abundant energy carrier in the cell. Its hydrolysis to ADP + Pi is exergonic, releasing energy that can drive endergonic reactions. ATP can also transfer energy by donating a phosphate group to other molecules, forming new covalent bonds, such as in the first step of glycolysis.

NADH acts as a reducing agent, donating two electrons to the electron transport chain, which results in the production of 3 ATP.

Redox reactions are central to metabolic pathways as they involve the transfer of electrons from an electron donor to an acceptor, facilitating energy production and conversion processes in the cell.

ATP is an energy carrier that provides energy for cellular processes, while NADH is an electron carrier that donates electrons during metabolic reactions, particularly in the electron transport chain.

Glycolysis is the first stage of both anaerobic and aerobic respiration, occurring in the cell cytosol. It converts one glucose (6-carbon) molecule into two pyruvate (3-carbon) molecules.

Glycolysis produces a net of two ATP molecules: two ATP are consumed in the first five steps and four ATP are produced in the later five steps.

Glycolysis is considered an ancient metabolic pathway because all living organisms can perform it, and it evolved prior to the oxygen environment, making it an anaerobic process.

The aldolase enzyme cleaves a C-C bond at step 4 of glycolysis, producing two 3-carbon structures from the 6-carbon glucose molecule.

1 Glucose + 2 NAD+ + 2 ADP + 2 Pᵢ → 2 pyruvate + 2 NADH + 2 H+ + 2 ATP

The main products of glycolysis are:

• 2 pyruvate
• 2 NADH
• 2 ATP

Hexokinase catalyzes the conversion of Glucose to Glucose 6-phosphate, using ATP to ADP in the process.

Phosphofructokinase-1 (PFK-1) is responsible for this conversion, also using ATP to ADP.

Glyceraldehyde 3-phosphate dehydrogenase catalyzes the conversion of Glyceraldehyde 3-phosphate to 1,3-Bisphosphoglycerate, producing NADH in the process.

A total of 2 ATP molecules are produced during glycolysis.

Dihydroxyacetone phosphate (DHAP) is converted to Glyceraldehyde 3-phosphate (G3P) by the enzyme Triosephosphate isomerase.

Mitochondria are the energy producers of the cell, responsible for aerobic respiration and ATP production.

Pyruvate is converted into acetyl CoA, producing CO2 and reducing NAD⁺ to NADH in the process.

1. Energy production using acetyl CoA for Kreb's cycle
2. Amino acid production using Kreb's cycle intermediates
3. Fatty acid synthesis by transporting acetyl CoA to the cytosol via citrate shuttle
4. Ketogenesis in the liver during low blood glucose states.

Acetyl CoA combines with oxaloacetate (four carbons) to begin the Kreb's cycle.

From one glucose molecule, the net result is 2 ATP, 6 NADH, and 2 FADH₂ produced from two cycles.

The substrates of the citric acid cycle are:

1. Oxaloacetate
2. Citrate
3. Isocitrate
4. α-ketoglutarate
5. Succinyl-CoA
6. Succinate
7. Fumarate
8. Malate

Flavoproteins are electron acceptors and donors, working as coenzymes in biochemical reactions. They contain derivatives of riboflavin and include FAD (Flavin adenine dinucleotide) and FMN (Flavin mononucleotide).

The Electron Transport Chain (ETC) transfers energy from electrons of reduced coenzymes (NADH or FADH2) to pump protons across the mitochondrial inner membrane, creating a proton gradient that drives ATP synthesis via ATP synthase through oxidative phosphorylation.

The proton gradient created by the ETC results in a proton-motive force that drives ATP synthase to convert ADP + Pi into ATP through the process of oxidative phosphorylation.

Chemiosmotic coupling refers to the mechanism by which the proton gradient established by the flow of electrons through the ETC provides the energy necessary for ATP synthesis by bonding phosphates to ADP.

The redox process in the ETC involves NADH losing electrons (oxidation) to become NAD⁺, while oxygen gains electrons (reduction) to form water, which is crucial for maintaining the flow of electrons and the overall function of the ETC.

The process is called oxidative phosphorylation because it involves the oxidation of NADH and FADH2, which leads to the phosphorylation of ADP to form ATP, utilizing the energy derived from the electron transport and the resulting proton gradient.

The net reactants and products of aerobic respiration are Glucose + O₂ → CO₂ + H₂O, which is a combustion reaction.

Complex I, also known as NADH:ubiquinone oxidoreductase, accepts NADH and pumps 4 protons (H⁺) into the intermembrane space.

Complex III, or ubiquinol-cytochrome c oxidoreductase, pumps 4 protons (H⁺) into the intermembrane space during electron transport.

ATP synthase synthesizes ATP by utilizing the proton gradient, pumping 3 protons (H⁺) into the matrix per 1 ATP produced.

NADH produced in glycolysis generates a net of 2 ATP after accounting for the transport costs into the mitochondria.

Each FADH2 generates 2 ATP during oxidative phosphorylation, as it pumps 6 protons (H⁺) across the membrane.

• Net Products: 2 NADH, 2 ATP
• Outcome: Transport (cost of 1 ATP each) followed by Oxidative Phosphorylation (O.P.) within the Electron Transport Chain (E.T.C.)

• GTP Produced: 2 GTP (converted to 2 ATP)
• NADH Produced: 6 NADH
• FADH2 Produced: 2 FADH2
• Outcome: Two turns of Kreb's cycle.

• ATP Yield: 119 ATP would be generated from a single pyruvate molecule when considering the complete oxidation through aerobic respiration.

Fermentation allows cells to regenerate NAD+ for continued glycolysis by reducing pyruvate to lactic acid in mammals, or to ethanol in yeast and microorganisms.

The Cori Cycle involves the release of lactate by muscles during high intensity exercise, which is then taken up by the liver and converted back into glucose through gluconeogenesis. This glucose is released into the blood and re-absorbed by the muscles for fuel.

In lactic acid fermentation, pyruvate is reduced to lactic acid, while in alcohol fermentation, pyruvate is first converted to acetaldehyde and then to ethanol. Both processes regenerate NAD+ from NADH.

The primary function of the PPP is to create NADPH and certain five carbon sugars (e.g., ribose).

The two branches of the PPP are:

1. Oxidative branch: Generates NADPH, essential for fatty acid synthesis.
2. Non-oxidative branch: Creates five carbon sugars, such as ribose for nucleotide synthesis.

Glucose-6-phosphate can enter the PPP instead of continuing through glycolysis, especially when nucleotide synthesis is not necessary.

NADPH is an electron carrier used in fat biosynthesis, the immune system, and preventing oxidative damage, while NAD+ is used in catabolic reactions such as glycolysis, pyruvate oxidation, and the Kreb's cycle.

The PPP is mainly active in the liver and adipocytes for lipid synthesis, but it is also active to some extent in all tissues.

Glycogenesis is the process of synthesizing glycogen from excess glucose when the body's immediate energy needs are met. It allows for the storage of glucose as glycogen, primarily in the liver and skeletal muscle cells, for short-term energy use.

The first step in glycogenesis involves converting glucose to glucose-6-phosphate, catalyzed by the enzyme hexokinase. This reaction traps glucose within the cell by adding a phosphate group.

Glucose-1-phosphate is formed by transferring the phosphate group from carbon 6 of glucose-6-phosphate to carbon 1, a reaction catalyzed by an enzyme during glycogenesis.

UTP (uridine triphosphate) provides the energy needed to cleave the phosphate group off glucose-1-phosphate, allowing glucose monomers to be added to an existing glycogen polymer via an a-1,4-glycosidic linkage.

Glycogen synthase catalyzes the addition of glucose monomers to an existing glycogen polymer through an a-1,4-glycosidic linkage.

When a glycogen polymer has more than 10 glucose residues, the branching enzyme cuts a 6 residue-long chain and attaches it via an a-1,6-glycosidic linkage, creating branches in the glycogen structure.

Insulin is released from the pancreas to facilitate glucose uptake by the cells. It triggers glucose transporters (GLUTs) to move to the cell membrane, allowing cells to readily take up glucose for metabolism.

When blood glucose levels are low, glucagon is released from the pancreas, signaling the liver to perform glycogenolysis, breaking down glycogen into glucose 1-phosphate (G1P), which is then converted into glucose 6-phosphate (G6P) for metabolism.

Glycogenolysis is the process of breaking down glycogen into glucose 1-phosphate (G1P) in response to low blood glucose levels. It is significant as it provides glucose for glycolysis, gluconeogenesis, or the pentose phosphate pathway, thus maintaining energy supply.

The liver responds to low blood glucose levels by increasing gluconeogenesis and ketogenesis, releasing energy molecules into the blood to provide energy for the body.

Epinephrine binds to receptors on hepatocytes, activating a signaling cascade that leads to the phosphorylation of glycogen phosphorylase, which then breaks down glycogen into glucose monomers.

Cortisol increases glycogen storage and gluconeogenesis in the liver, while decreasing glycogen storage and inhibiting glucose uptake in muscle. It also inhibits insulin secretion, altering blood sugar and carbohydrate metabolism.

In the absence of insulin, only the nervous system (including the brain) and the liver continue to absorb glucose.

Gluconeogenesis is the metabolic synthesis of glucose from non-carbohydrate precursors. Common substrates include lactate (Cori cycle), glycerol (from triglyceride breakdown), glucogenic amino acids (e.g., alanine), and TCA cycle intermediates (e.g., oxaloacetate). Odd-chain fatty acids can contribute via propionyl-CoA → succinyl-CoA, but even-chain fatty acids and acetyl-CoA cannot be converted to net glucose.

Gluconeogenesis bypasses the irreversible steps of glycolysis using these enzymes:

• Glucose-6-phosphatase: converts glucose-6-phosphate → glucose.
• Fructose-1,6-bisphosphatase: converts fructose-1,6-bisphosphate → fructose-6-phosphate.
• Pyruvate carboxylase: converts pyruvate → oxaloacetate (uses ATP).
• PEP carboxykinase (PEPCK): converts oxaloacetate → phosphoenolpyruvate (uses GTP).

(Note: pyruvate carboxylase uses ATP; PEPCK uses GTP.)

Fatty acids and acetyl CoA cannot be used to produce glucose because:

• Fatty acids are catabolized in β-oxidation into acetyl CoA, which is a two-carbon unit and cannot provide the net three-carbon precursors required for gluconeogenesis.
• Acetyl CoA entering the TCA cycle is typically decarboxylated, so it cannot serve as a net carbon source for glucose synthesis (except for odd-chain fatty acids that yield propionyl-CoA).

The combination of glycogenolysis and gluconeogenesis is crucial for maintaining blood glucose levels, ensuring a steady supply of glucose for energy, especially during fasting or intense exercise.

Hexokinase catalyzes the conversion of Glucose to Glucose 6-phosphate, using ATP and producing ADP in the process.

Fructose 1,6-bisphosphate is converted to Dihydroxyacetone phosphate and Glyceraldehyde 3-phosphate by the enzyme aldolase.

The enzyme phosphoenolpyruvate carboxykinase catalyzes the conversion of Phosphoenolpyruvate to Oxaloacetate, utilizing CO2 and producing GDP and GTP.

Fructose 1,6-bisphosphatase catalyzes the conversion of Fructose 1,6-bisphosphate back to Fructose 6-phosphate, which is a key regulatory step in gluconeogenesis.

The final product of glycolysis is Pyruvate, which is formed from Oxaloacetate through a series of enzymatic reactions.

Fatty acid synthesis produces building blocks used to form membrane lipids (e.g., phospholipids and sphingolipids) and storage lipids (triacylglycerols/triglycerides).

Malonyl CoA (3C) is a temporary intermediate that is produced by adding CO2 to make the substrate more reactive, allowing the addition of acetyl CoA (2C) to the growing fatty acid chain.

The primary enzyme complex involved in fatty acid synthesis is called fatty acid synthase.

The typical end product of fatty acid synthesis is palmitate (C16).

The substrates required for fatty acid synthesis include NADPH, acetyl CoA, and ATP.

Fatty acids in triglycerides store energy in adipose tissue.

Unsaturated fats store less energy and take up more space than saturated fats, which is why the body prefers to store saturated fats in triglycerides.

1. Oxidation in the TCA (Krebs) cycle to produce ATP.
2. Conversion into ketone bodies via ketogenesis in the liver during fasting.
3. Use as a substrate for biosynthesis (e.g., fatty acid synthesis and cholesterol/sterol synthesis).

β-oxidation is the process where fatty acids are oxidized two carbons at a time to form acetyl-CoA. It involves the activation of fatty acids to acyl-CoA and then cleavage in the mitochondrial matrix.

The last three carbons of fatty acids with an odd number of carbons are used as a substrate for gluconeogenesis.

1. Activation: Fatty acids are converted to acyl-CoA by acyl-CoA synthetase at the outer mitochondrial membrane (costs the equivalent of 2 ATP: ATP → AMP + PPi).
2. Mitochondrial β-oxidation: Acyl-CoA undergoes repeated cycles (oxidation, hydration, oxidation, thiolysis) in the matrix, cleaving two-carbon acetyl-CoA units that enter the TCA cycle; FADH2 and NADH are produced during the cycles.

Ketone bodies, also known as ketones, are produced in the liver from the breakdown of fatty acids into acetyl CoA during starvation. In the absence of insulin, some acetyl CoA is converted into ketones within the mitochondria of liver cells, which then travel to other tissues to be used as an alternative energy source.

The three primary ketone bodies produced in humans are:

1. Acetone
2. Acetoacetic acid
3. β-hydroxybutyrate

Ketone bodies cannot be used as substrates for gluconeogenesis because they do not provide the necessary precursors for glucose synthesis, which primarily requires substrates like lactate, glycerol, and certain amino acids.

Ketogenesis is associated with low insulin levels. It occurs when insulin is low, such as during starvation, leading to the conversion of acetyl CoA into ketone bodies in the liver.

Ketone bodies have a carbonyl group, which is very polar. This polarity allows them to dissolve in blood and move easily throughout the body without the need for carrier proteins.

The sweet smell associated with ketosis is due to the presence of ketone bodies in the breath, particularly acetone, which has a fruity odor. This occurs when a person is starving and in a state of ketosis.

Potential downsides of the keto diet include:

• Nutrient deficiencies due to the removal of most plant-based foods and their micronutrients.
• Weight regain after returning to carbohydrate consumption.
• It may only serve as a short-term physiological hack for weight loss.

Protein formation, or anabolism, occurs mainly during the fed state and is associated with glycolysis, glycogenesis, and lipid storage.

Protein breakdown, or catabolism, occurs mainly during the fasting state and is associated with gluconeogenesis, glycogenolysis, β-oxidation, and ketogenesis.

The enzymes involved include brush-border enzymes (like amino-peptidase) and pancreatic enzymes (such as trypsin, chymotrypsin, and carboxypeptidase).

The nitrogen group is removed, producing ammonia and a carbon chain. The ammonia is then fed into the liver urea cycle to become urea, which can be excreted in urine by the kidneys.