Comprehensive Guide to Human Metabolism and Metabolic Pathways

Posted on May 13, 2024 in Biology

1. Glycolysis

• Location: Cytosol
• Oxidizing agent: NAD⁺, which is reduced to NADH

Steps:

1. Glucose is converted to Glucose-6-Phosphate (G-6-P) by Hexokinase, consuming ATP (ATP → ADP).
2. G-6-P is converted to Fructose-6-Phosphate (F-6-P) by Phosphoglucoisomerase.
3. F-6-P is converted to Fructose-1,6-Bisphosphate (F-1,6-BP) by Phosphofructokinase, consuming ATP (ATP → ADP).
4. F-1,6-BP is cleaved by Aldolase into two products: Glyceraldehyde-3-Phosphate and Dihydroxyacetone Phosphate (DHAP).
5. DHAP is converted to Glyceraldehyde-3-P by Triose Phosphate Isomerase.
6. Glyceraldehyde-3-P is converted to 1,3-Bisphosphoglycerate by Glyceraldehyde-3-P Dehydrogenase, reducing NAD⁺ and incorporating inorganic phosphate (NAD⁺ + Pi → NADH + H⁺).
7. 1,3-Bisphosphoglycerate is converted to 3-Phosphoglycerate by Phosphoglycerate Kinase, producing ATP (ADP → ATP).
8. 3-Phosphoglycerate is converted to 2-Phosphoglycerate by Phosphoglycerate Mutase.
9. 2-Phosphoglycerate is converted to Phosphoenolpyruvate by Enolase, producing ATP (ADP → ATP).
10. Phosphoenolpyruvate is converted to Pyruvate by Pyruvate Kinase, producing ATP (ADP → ATP).

Possible Pathways for Pyruvate:

1. Conversion to Acetyl-CoA by Pyruvate Dehydrogenase, entering the Krebs cycle.
2. Conversion to Lactate by Lactate Dehydrogenase.
3. Conversion to Ethanol by Alcohol Dehydrogenase.

Energy Yield:

• 2 ATP per glucose molecule
• 2 NADH per glucose molecule
• 2 Pyruvate molecules per glucose molecule

Regulation:

Allosteric Regulation:

• Phosphofructokinase-1 (PFK-1): Inhibited by ATP and citrate, activated by AMP and Fructose-2,6-Bisphosphate (F-2,6-BP).
• Hexokinase: Inhibited by G-6-P.
• Glucokinase: Inhibited by F-6-P.

Covalent Regulation:

• Glucagon increases cAMP levels, activating Protein Kinase A, which phosphorylates Pyruvate Kinase, leading to its inactivation.

2. Gluconeogenesis

• De novo synthesis of glucose from non-carbohydrate sources.
• Location: Liver and kidney
• Occurs in both the cytosol and mitochondria.

Steps:

1. Pyruvate is converted to Oxaloacetate by Pyruvate Carboxylase in the mitochondria, consuming ATP and requiring biotin (ATP → ADP + Pi).
2. Oxaloacetate is converted to Malate by Malate Dehydrogenase in the mitochondria, oxidizing NADH (NADH + H⁺ → NAD⁺).
3. Malate is transported to the cytosol and converted back to Oxaloacetate by Malate Dehydrogenase, reducing NAD⁺ (NAD⁺ → NADH + H⁺).
4. Oxaloacetate is converted to Phosphoenolpyruvate by Phosphoenolpyruvate Carboxykinase, consuming GTP (GTP → GDP + CO₂).
5. The remaining steps are reversible and follow the reverse of glycolysis until Fructose-1,6-Bisphosphate.
6. F-1,6-BP is converted to Fructose-6-Phosphate by Fructose-1,6-Bisphosphatase.
7. F-6-P is converted to Glucose-6-Phosphate by Phosphoglucose Isomerase.
8. G-6-P is converted to Glucose by Glucose-6-Phosphatase.

Energy Consumption:

• 2 Pyruvate molecules are required to synthesize 1 glucose molecule.
• 2 ATP are consumed by Pyruvate Carboxylase (2 x 1 ATP = 2 ATP).
• 2 GTP are consumed by PEP Carboxykinase (2 x 1 GTP = 2 GTP).
• 2 ATP are consumed by Phosphoglycerate Kinase (2 x 1 ATP = 2 ATP).
• Total energy consumption: 6 ATP equivalents.

Regulation:

Allosteric Regulation:

• Fructose-1,6-Bisphosphatase: Inhibited by AMP and F-2,6-BP (which also activates glycolysis).

Covalent Regulation:

• Glucagon increases cAMP levels, activating Protein Kinase A, which phosphorylates F-1,6-BPase, leading to its activation.
• Insulin activates Protein Phosphatase, which dephosphorylates F-1,6-BPase, leading to its inactivation.

3. Glycogen Synthesis and Degradation

Synthesis:

• Glycogen is a storage polysaccharide.
• Location: Liver and muscles
• Liver glycogen releases glucose into the blood, while muscle glycogen does not.
• Occurs in the cytosol.

Steps:

1. Glucose is converted to G-6-P by Hexokinase (in muscle) or Glucokinase (in liver).
2. G-6-P is converted to Glucose-1-Phosphate (G-1-P) by Phosphoglucomutase.
3. G-1-P reacts with UTP to form UDP-glucose and Pyrophosphate (PPi) by UDP-glucose Pyrophosphorylase.
4. UDP-glucose adds a glucose unit to a growing glycogen chain (n residues) to form a chain with n+1 residues by Glycogen Synthase. This enzyme requires a primer, which is provided by Glycogenin. This forms α-1,4 glycosidic bonds.
5. The Branching Enzyme elongates the glycogen chain and forms α-1,4 and α-1,6 glycosidic bonds, creating branches.

Degradation:

• Glycogen degradation occurs via phosphorolysis.

Steps:

1. Glycogen Phosphorylase removes a glucose unit from the non-reducing end of a glycogen chain (n residues) as G-1-P, leaving a chain with n-1 residues.
2. The Debranching Enzyme has two activities:
   • Transferase: Shifts three glycosyl units to the next branch.
   • α-1,6-Glucosidase: Cleaves α-1,6 glycosidic bonds at branch points.
3. G-1-P is converted to G-6-P by Phosphoglucomutase.
4. G-6-P can have two fates:
   • Conversion to Pyruvate via glycolysis.
   • Conversion to Glucose by Glucose-6-Phosphatase (in liver) for release into the blood.

Regulation:

Covalent Regulation:

• Glycogen Phosphorylase: Phosphorylated form is active, dephosphorylated form is inactive.
  • In the liver, glucagon increases cAMP levels, leading to phosphorylation and activation of Glycogen Phosphorylase.
  • In muscles, epinephrine increases cAMP levels, leading to phosphorylation and activation of Glycogen Phosphorylase.
• Glycogen Synthase: Phosphorylated form is inactive, dephosphorylated form is active.
  • Insulin activates Glycogen Synthase by promoting dephosphorylation.
  • Epinephrine and glucagon inhibit Glycogen Synthase by promoting phosphorylation.

4. Fructose and Galactose Metabolism

Fructose:

• Sources: Fruit, honey, sucrose

Metabolism in Muscle:

1. Fructose is converted to F-6-P by Hexokinase.
2. F-6-P enters glycolysis.

Metabolism in Liver:

• The liver has low Hexokinase activity.

1. Fructose is phosphorylated to Fructose-1-Phosphate (F-1-P) by Fructokinase, consuming ATP (ATP → ADP).
2. F-1-P is cleaved by Aldolase into two products: Glyceraldehyde and DHAP.
   • Glyceraldehyde is converted to Glyceraldehyde-3-P by Glyceraldehyde Kinase, consuming ATP (ATP → ADP), and enters glycolysis.
   • DHAP is converted to Glyceraldehyde-3-P by Triose Phosphate Isomerase and enters glycolysis.

Galactose:

• Metabolized in the liver.
• Epimer of glucose (difference at C4)

Steps:

1. Galactose is converted to Galactose-1-Phosphate by Galactokinase, consuming ATP (ATP → ADP).
2. Galactose-1-P reacts with UDP-glucose to form G-1-P and UDP-galactose by Galactose-1-Phosphate Uridyl Transferase.
3. UDP-galactose is converted to UDP-glucose by UDP-Galactose-4-Epimerase.
4. G-1-P is converted to G-6-P by Phosphoglucomutase and enters glycolysis.

• UDP-galactose is a high-energy compound.

5. Pentose Phosphate Pathway

• Location: Liver, mammary glands, adipose tissue, adrenal cortex
• Occurs in the cytosol.
• Products: NADPH (important for fatty acid and cholesterol synthesis) and Ribose-5-Phosphate (R-5-P)
• Three phases: Oxidative, Isomerization, Non-oxidative

Oxidative Phase (Irreversible):

1. G-6-P is converted to 6-Phosphogluconolactone by G-6-P Dehydrogenase, producing NADPH (NADP⁺ → NADPH + H⁺).
2. 6-Phosphogluconolactone is converted to 6-Phosphogluconate by Lactonase, consuming water (H₂O → H⁺).
3. 6-Phosphogluconate is converted to Ribulose-5-Phosphate by 6-Phosphogluconate Dehydrogenase, producing NADPH (NADP⁺ → NADPH + H⁺).

Isomerization Phase:

• Ribulose-5-P can be converted to R-5-P by Phosphopentose Isomerase.
• Ribulose-5-P can also be converted to Xylulose-5-P by Ribulose-5-Phosphate Epimerase.

Non-oxidative Phase (Reversible):

1. Xylulose-5-P and R-5-P are converted to Glyceraldehyde-3-P and Sedoheptulose-7-P by Transketolase.
2. Glyceraldehyde-3-P and Sedoheptulose-7-P are converted to F-6-P and Erythrose-4-Phosphate by Transaldolase.
3. Erythrose-4-Phosphate and Xylulose-5-P are converted to F-6-P and Glyceraldehyde-3-P by Transketolase.

Regulation:

• High NADPH needs activate the oxidative phase, directing F-6-P and Glyceraldehyde-3-P towards gluconeogenesis to produce more glucose for the oxidative phase.
• High R-5-P needs promote the conversion of F-6-P and Glyceraldehyde-3-P from glycolysis to R-5-P.
• Key enzyme: G-6-P Dehydrogenase is activated by increased NADP⁺ levels.

6. Triacylglycerol (TAG) Synthesis and Degradation

Synthesis:

• TAGs are esters of glycerol and three fatty acids.
• Location: Liver and adipose tissue
• Storage: Adipose tissue
• TAGs are the main energy source.

Synthesis in Liver:

1. Glucose is converted to DHAP, which is then converted to Glycerol-3-Phosphate by Glycerol-3-Phosphate Dehydrogenase, oxidizing NADH (NADH + H⁺ → NAD⁺).
2. Glycerol can also be directly phosphorylated to Glycerol-3-Phosphate by Glycerol Kinase.
3. Glycerol-3-Phosphate is converted to Phosphatidic Acid by Acyl Transferase.
4. Phosphatidic Acid is converted to TAG.

Synthesis in Adipose Tissue:

• Similar to liver synthesis, but adipose tissue lacks Glycerol Kinase, so glycerol cannot be directly used for TAG synthesis.

Degradation:

• Two pathways for TAG degradation:

1. TAG is hydrolyzed to Glycerol and Fatty Acids.
   • Glycerol is converted to Glycerol-3-Phosphate by Glycerol Kinase, consuming ATP (ATP → ADP).
   • Glycerol-3-Phosphate is converted to DHAP by Glycerol-3-Phosphate Dehydrogenase, reducing NAD⁺ (NAD⁺ → NADH + H⁺).
   • DHAP can enter glycolysis or gluconeogenesis.
2. TAG is hydrolyzed to Fatty Acids.
   • Fatty Acids are converted to Acetyl-CoA by β-oxidation, which enters the Krebs cycle.
   • Alternatively, fatty acids can be converted to Acetoacetate, which forms ketone bodies.

Regulation:

• Epinephrine and glucagon increase cAMP levels, activating Protein Kinase A, which phosphorylates Hormone-Sensitive Lipase, increasing its activity and promoting lipolysis (TAG degradation).
• Insulin decreases cAMP levels, leading to dephosphorylation and inactivation of Hormone-Sensitive Lipase, decreasing its activity and inhibiting lipolysis.

7. Fatty Acid Degradation (β-Oxidation)

• Location: Mitochondria

Activation (in Cytosol):

1. Fatty Acid + ATP + CoA → Acyl-CoA + AMP + PPi (catalyzed by Acyl-CoA Synthetase)

Transport of Fatty Acids into Mitochondria: Carnitine Shuttle

1. Acyl-CoA + Carnitine → Acylcarnitine + CoA-SH (catalyzed by Carnitine Acyl Transferase I)
2. Acylcarnitine is transported across the mitochondrial membrane by Acylcarnitine Translocase.
3. Inside the mitochondrial matrix:
   1. Acylcarnitine → Carnitine + Acyl-CoA (catalyzed by Carnitine Acyl Transferase II)
   2. CoA-SH is regenerated.

β-Oxidation (in Mitochondria):

1. Acyl-CoA → Enoyl-CoA (catalyzed by Acyl-CoA Dehydrogenase, reducing FAD to FADH₂) (Oxidation)
2. Enoyl-CoA → 3-Hydroxyacyl-CoA (catalyzed by Enoyl-CoA Hydratase, adding water) (Hydration)
3. 3-Hydroxyacyl-CoA → 3-Ketoacyl-CoA (catalyzed by 3-Hydroxyacyl-CoA Dehydrogenase, reducing NAD⁺ to NADH + H⁺) (Oxidation)
4. 3-Ketoacyl-CoA → Acyl-CoA + Acetyl-CoA (catalyzed by β-Ketothiolase, using CoA-SH) (Thiolysis)

Energy Yield:

• One cycle of β-oxidation produces Acetyl-CoA, FADH₂, and NADH + H⁺.
• Electron transport chain: NADH yields 3 ATP, FADH₂ yields 2 ATP.
• Krebs cycle: Acetyl-CoA yields 12 ATP.
• Total energy yield from one cycle of β-oxidation: 17 ATP.
• Complete oxidation of Palmitic Acid (16 carbons) yields 129 ATP (8 Acetyl-CoA, 7 NADH + H⁺, 7 FADH₂).

Regulation:

• Availability of fatty acids
• Source of fatty acids is TAG in adipose tissue, regulated by Hormone-Sensitive Lipase.
• Epinephrine and glucagon increase fatty acid degradation.
• Insulin decreases fatty acid degradation.

8. Fatty Acid Synthesis

• Location: Liver and mammary glands
• Occurs in the cytosol.

Steps:

1. Transport of Acetyl-CoA from mitochondria to cytosol:
   • Acetyl-CoA + Oxaloacetate → Citrate (in mitochondria)
   • Citrate is transported to the cytosol.
   • Citrate → Acetyl-CoA + Oxaloacetate (catalyzed by ATP Citrate Lyase, consuming ATP)
   • Oxaloacetate returns to the mitochondria.
2. Acetyl-CoA → Malonyl-CoA (catalyzed by Acetyl-CoA Carboxylase, consuming ATP and requiring biotin) (ATP → ADP + Pi)
3. Formation of Acetyl-ACP and Malonyl-ACP:
   • Acetyl-CoA → Acetyl-ACP (catalyzed by Acetyl Transacylase, using ACP)
   • Malonyl-CoA → Malonyl-ACP (catalyzed by Malonyl Transacylase, using ACP)
4. Elongation steps:
   1. Acetyl-ACP + Malonyl-ACP → Acetoacetyl-ACP (catalyzed by Acyl-Malonyl ACP Condensing Enzyme, releasing CO₂) (Condensation)
   2. Acetoacetyl-ACP → 3-Hydroxybutyryl-ACP (catalyzed by β-Ketoacyl ACP Reductase, oxidizing NADPH + H⁺ to NADP⁺) (Reduction)
   3. 3-Hydroxybutyryl-ACP → Crotonyl-ACP (catalyzed by 3-Hydroxyacyl ACP Dehydratase, releasing water) (Dehydration)
   4. Crotonyl-ACP → Butyryl-ACP (catalyzed by Enoyl ACP Reductase, oxidizing NADPH + H⁺ to NADP⁺) (Reduction)
   5. Steps 1-4 are repeated seven times to produce Palmitate (16 carbons).

Essential Fatty Acids:

• Linoleic acid
• Linolenic acid

Energy Consumption:

• Synthesis of one Palmitic Acid molecule requires 8 Acetyl-CoA, 7 Malonyl-CoA, and 14 NADPH + H⁺.

Regulation:

Allosteric Regulation:

• Acetyl-CoA Carboxylase: Activated by citrate, inhibited by acyl-CoA (especially palmitoyl-CoA).

Covalent Regulation:

• Glucagon and epinephrine inhibit fatty acid synthesis by inhibiting Protein Phosphatase.
• Insulin stimulates fatty acid synthesis by activating Protein Phosphatase.

Sources of Acetyl-CoA:

• Degradation of fatty acids
• Oxidation of pyruvate
• Degradation of ketogenic amino acids

9. Complex Lipids

• Esters of fatty acids with alcohols and other molecules.
• Lipid membranes are amphipathic, having both hydrophilic and hydrophobic regions.
• Major components of membranes:

1. Glycerophospholipids
2. Sphingolipids
3. Sterols

Glycerophospholipids:

• Glycerol backbone
• Two fatty acids
• Phosphoric acid residue
• Alcohol (e.g., choline, ethanolamine, inositol)
• Simplest glycerophospholipid: Phosphatidic Acid
• Examples: Phosphatidylcholine, Phosphatidylethanolamine, Phosphatidylinositol

Sphingolipids:

• Sphingosine backbone
• Phosphoric acid residue (with choline or ethanolamine)
• Fatty acid
• Alcohol
• Example: Sphingomyelins

Glycolipids (Glycosphingolipids):

• Ceramide + carbohydrate
• Examples:
  • Cerebrosides (e.g., Galactocerebrosides with one galactose residue)
  • Gangliosides (derived from sphingosine, containing carbohydrates and sialic acid residues)

Cardiolipin:

• Two phosphatidic acid molecules attached to glycerol through phosphate groups.

Lipoproteins:

• Lipids + proteins (non-covalent interactions)
• Globular, micelle-like structures
• Hydrophobic core of TAGs and cholesterol esters
• Hydrophilic surface of apoproteins, phospholipids, and unesterified cholesterol
• Transport non-polar lipids in the blood
• Apoproteins solubilize lipids and target lipoproteins to tissues.

10. Degradation of Amino Acids

• Deamination: Removal of the amino group as ammonia (NH₃)

Transamination:

• α-Amino Acid + α-Ketoglutarate ↔ Glutamate + α-Keto Acid (catalyzed by Transaminases, requiring pyridoxal-5-phosphate as a cofactor)
• Examples:
  • Aspartate + α-Ketoglutarate ↔ Oxaloacetate + Glutamate (catalyzed by Aspartate Aminotransferase)
  • Alanine + α-Ketoglutarate ↔ Pyruvate + Glutamate (catalyzed by Alanine Aminotransferase)

Oxidative Deamination:

• Glutamate (from transamination) is converted to α-Ketoglutarate and NH₃.
• Glutamate → α-Ketoglutarate + NH₃ (catalyzed by Glutamate Dehydrogenase, reducing NAD⁺ to NADH + H⁺)

Essential Amino Acids:

• Isoleucine (Ile), Leucine (Leu), Lysine (Lys), Methionine (Met), Phenylalanine (Phe), Threonine (Thr), Tryptophan (Trp), Valine (Val)

Non-Essential Amino Acids:

• Alanine (Ala), Asparagine (Asn), Aspartate (Asp), Cysteine (Cys), Glutamate (Glu), Glutamine (Gln), Glycine (Gly), Proline (Pro), Serine (Ser), Tyrosine (Tyr)

Semi-Essential Amino Acids:

• Arginine (Arg), Histidine (His)

11. Detoxification of Ammonia (Urea Cycle)

• Removal of excess nitrogen from the body as urea.
• Location: Liver (urea synthesis), excretion by kidney
• Occurs in both the cytosol and mitochondria.
• Energy consumption: 3 ATP per urea molecule

Steps:

1. NH₃ + CO₂ + 2 ATP → Carbamoyl Phosphate + 2 ADP + Pi (catalyzed by Carbamoyl Phosphate Synthetase I, key regulatory step) (Mitochondria)
2. Carbamoyl Phosphate + Ornithine → Citrulline (catalyzed by Ornithine Transcarbamylase, releasing Pi) (Mitochondria)
3. Citrulline is transported to the cytosol.
4. Citrulline + Aspartate → Argininosuccinate (catalyzed by Argininosuccinate Synthetase, consuming ATP) (ATP → AMP + PPi) (Cytosol)
5. Argininosuccinate → Arginine + Fumarate (catalyzed by Argininosuccinase) (Cytosol)
6. Arginine → Ornithine + Urea (catalyzed by Arginase, consuming water) (Cytosol)
7. Ornithine returns to the mitochondria.

• Nitrogen atoms in urea come from aspartate and carbamoyl phosphate.

Regulation:

-to maintain/control -Types(availability of substrate, amount of enz, allostericXcovalent, hormone reg). #covalent (ezymes=phosphorylation/dephos à modification of enzyme activitiy, often for hydrophilic hormones) #allosteric (cofactors, activators, inhibitors, often inhibited by end product) #hormonal (lipophilic= influence of transcription, hydrophilic= use of 2^nd msgr cAMP eg: epinephrine).

20.2.Thermodynamics: -Change of d-G (processes under constant P and T) -depends on availability of substrate & need of pdts -dG0 (endergonic) =nonspontaneous (deliver energy) -dG=0 (balance) =no reaction -ex: Glucose+Pi à G-6-P + H2o (endergonic) -ATP àADP+Pi (exergonic) -Glucose+ATPà G-6-P + ADP (exergo) #ATP (high energy) -Source (oxidative phos, regeneration of ADP) -Use (active transp, cell signalling, synth of dna/rna) #other high energy phosphates (carbamoyl phosphate, phosphoenolpyruvate) -Thiol esters (acetylCoA, UDP-glucose).

21.3.AA, peptides, proteins: -Building blocks of proteins -in body (20 esential AA) #Non-polar (hydrophobic) = Gly, Ala, Val, Leu, Isol, Met, Trp, Phe, Pro #Polar = Ser, Thr, Cys, Tyr, Asn, Gln. #Acidic = Asp acid, Glu acid. #Basic = Lys, Arg, His #unusualAA= Ornithine, citrulline, GABA  #Peptides: Linkage of AA’s w/ covalent bond (peptide bond) -by condensation reaction of carboxylic group of AA & Amino grp of another AA & removal of H2O -Planar structure -Short polymers of AA ex: Dipeptide (2AA) -Tri (3AA) -Oligo(+10AA) #Proteins: -Polypeptides (covalently linked alpha-AA) + Possibly cofactors, coenzymes, prosthetic groups -Functions (transport&storage, contractile, structural, regulatory) #Simple proteins: only polypeptide chain(enzymes, albumin, keratin) #Complex proteins: -polypeptide chain+nonpeptidic component (glycoprotein) -Lipoproteins -Phosphoproteins  -Hemoproteins #Formation: geneàtranscàtaslaàprotein #Deg: In lysosomes, cytoplasm
4. Structure of Proteins: 1=  Sequence/ order of AA, bounded by peptide -Reading from N terminus to C terminus (covalent peptide bonds) 2= Alpha-helix, beta-sheets (non-covalant bonds) -peptide bonds are planar -alpha-helix (right handed, peptide bond) -beta-sheets (H-bonds, very stable) 3=  3D structure(non-covalant, disulphide bridges) -setting sec. struc in space -3D predetermined by sec. struc 4= final conformation -(polypeptide chains) -most stable struc. #Types: 1. Fibrous (very solid) 2.Globular (spherical). #Fuction is determined by 3D structure #Denaturation: destruction of 2^nd, 3^rd, 4^th structures (loss of conformation) causes, temp, ph, chemical cmpds,

22.5.Enzymes, enz Kinetics: #Enz: -Biological catalysts that speeds up a chemical reaction by lowering the activation energy  -Active site (catalytic part, binding part/ lock&key hypothesis) -Allosteric site *Multienzyme complex= several enzymes -catalyzes complex of reactions (high efficiency, less side reactions, complex regulations)ex: pyruvate dehydrogenase complex *AA that have catalytic function in active site (Tyr, Lys, Asp, Cys, His, Asp) *Active site (proximity effect, high concentration). 
 #Kinetics = study of rates of enzymatic reaction under diff conditions #Rates against concentration of substrates: -Micheals-menten equ: V=Vmax.(s)/Km+s -Kinetic parameters -Km(Michaelis constant): concentration of substrate at half max velocity (Vmax/2) -Maximum velocity(Vmax): max achievable rate of reaction under defined conditions  #Rates against environment: inc. temp = inc. velocity à denaturation = 50 (optimum 37), PH, Ionic strength (bonds), redox #Rates against amount of enzyme: -inc. amount = inc. Vmax, Km constant #Rates against effectors: Activators = inc. enzymatic activity, Inhibitors = Dec. enzymatic activity.

23.6.Ezymes, Inhibition: #Competitive: Bind to enz active siteàblocks binding of substrate -Structurally similar to substrate -Enouch conc. of substrate = removal inhibition -Presence of inhibitor=(Km Inc., Vmax, same) #Noncomp: -Bind to allosteric site of enzyme or enzyme w/ substrate = changes conformation & blocks activity -Inhibition removal not possible by inc. conc. of substrate -Presence of inhibitor=(Km same, Vmax inc.) #Uncomp: -Binds to complex enzyme, usually mixed inhibitors -Parallel lines -Presence of inhib= (Km dec., Vmax dec).

24.7.Enzymes, reg. of enz activity: #Allosteric= -Conformation changes after ligand binding (activators&inhibitors) -Allosteric inhib distorts active site -Allosteric activator brings substrate to active site-More units of enzymeàcooperationàsigmoid saturation curve(ex:haemoglobin) -Feedback process (frequent, inhibition by end product of metabolic pathway) -Aspartate transcarbamylase ex of allosteric reg -Quick regulation (s). #Covalent: -Attachment of phosphoral group on enzymeàchanges conformation -Protein kinase typically catalyse transfer of phosphoral group from ATP to enzyme. Protein phosphatase reverse the transfer (Activation/deactivation)
Quick regulation(m)  Mechanism of hydrophilic hormones (insulin, glucagon, epinephrine) -Enzyme+ATPßàEnzyme-P+ADP (protein kinaseà, protein phosphataseß).

25.8.Fate of Pyruvate: #Anaerobic state (cytosol): – Lactic acid fermentation = Pyruvate ßàLactate (lactate dehydrogenase, NADH+H+àNAD+) -Ethanol fermentation = PyruvateàAcetylaldehyde (CO2 out, pyruvate decarboxylase)àEthanol (NADH+H+àNAD+, alcohol dehydrogenase) #Aerobic(mitochondria): 1. Oxidative decarboxylation= Pyruvate +NAD++ CoA àAcetylCoA + CO2+ NADH (Pyruvate dehydrogenase) 2.Oxidative carboxylation = Pyruvate ßà Oxaloacetate (Pyruvate carboxylase, ATP+BiotinàADP+Pi) 3.Reducing carboxylation = Pyruvate ßà Malate (malate dehydro, NADPH+H+BiotinàNADP+).  #Cori cycle: Transport of lactate from muscle tissue to liverà resenthesis of glucose by gluconeogenesis à return of glucose to muscle tissue.

26.9.Fate of Acetyl-CoA: #Ketone bodies(from FA deg.) -Alt source of energy (starvation) -Liver mitochondria = 2X AcetylCoA ßà AcetacetylCoA (thiolase, CoAsh out) à HMG-CoA (HMG-CoA synthase, +h2o, acetylCoAàCoAsh)à Acetoacetate (HMG-CoA lyase, acetylCoA out)à 2prdts = 1. 3-Hydroxybutarate (3-hydroxy butatrate dehydro, NADH+H+àNAD+) / Acetone.  *3-hydroxybutarate is transformed back into citric acid cycle* -Other fates = Cholesterol/steroids synth, Krebs cycle, Lipolysis. #Krebs: AcetylCoA+ OxaloacetateàCitrate (citrate synthase) àIsocitrate (aconitase) àalpha-ketoglutarate (NAD+àNADH+H+, CO2 out) àSuccinylCoA (alpha-ketoglutarate dehydrogenase, NAD+àNADH+H+, CoAshàCO2)àSuccinate (succinate thiokinase, GDPàGTP, CoAsh out)àFumarate (succinate dehydro, FADàFADH2) àMalate (fumarase, +h2o)àOxaloacetate (malate dehydro, NAD+àNADH+H+) #Energy= 3NADH(3ATP =9ATP), 1FADH2 (2ATP= 2ATP), 1GTP(1ATP) = 12 ATP/ 1 glucose.

27.10.Metabolisms of nutrients and it’s changes: Mainly carbohydrates, lipids, proteins. -High food intake= storage (glycogen, lipids). Classified into 1.Catabolism = degradation (glycolysis, glycogenesis, lipolysis, oxi FA) -breakdown of molecules into smaller units= energy released 2. Anabolism = biosynthesis (gluconeogenesis, synthesis of glucagon, synthesis of FA, lipogenesis) -building cmpds from smaller molecules to larger ones = energy used. #Well fed state: (allosteric, covalent) -Activation of glycolysis, synthesis of glucagon, synthesis of FA&TAG) -Inhibition (gluconeogenesis, beto-oxidation of FA, degradation of glycogen&TAG). #Short starvation: (allosteric, covalent) -Act (degradation of glycogen, gluconeogenesis) #Long starvation:(allosteric, covalent) -Act (gluconeogenesis from AA&glycerol, degradation of TAG&FA, synthesis of ketone bodies).

28.11.Lipoproteins: -Noncovalent interactions between lipids&proteins (hydrophobic core, hydrophilic surface) -Transport of non-polar lipids in blood #Types depending on size, density, composition of lipids: 1. Low-density lipoproteins (LDL) -formed from VLDLàIDLàLDL -highest in cholesterol (transport cholest to tissues) -Low TAG 2. Very low-density lipoproteins (VLDL):  -high TAG (transport of lipids from liveràtissues) -Low cholesterol. 3. High-density lipoproteins (HDL): -highest density lipoprotein -Lowest TAG -High cholesterol -deliver cholesterol to liver for elimination 4. Chylomicrons (CM): -Highest TAG -Lowest cholesterol -transport of lipids from foodàliver -contains mainly TAG 5. Lipoprotein Lipase (LPL): -Degradation of TAG à high content of cholesterol (TAGàGlycerol+FA (LPL)).

29.12.Respiratory chain: -ETC -4 major protein complexes -Inner mitochondrial membrane=highly impermeable -Electrons from catabolic pathways (glycolysis, citrate acid cycle) -Composed of complexes I-IV + coenzyme Q  & cytochrome C. #Complex I (NADH-Q oxidoreductase): -Transport of e from NADH+H+ to CoenzymeQ = FMN + NADH à FMNH2 + NAD+ àeàFe-SàCoenzymeQ #Cplx II (Succinate-Q reductase) = transport of e from FADH2 à CoenzymeQ #Cplx III (Q-cytochrome C reductase)= transport of e from UQH2 to Cytochrome C #Cplx IV (Cytochrome C oxidase)key step = receive electrons from Cytochrome C -e used to reduce O2àH2O **Cytochrome C transfer e from III & IV** -I, II, III = high H+ gradient.

30.13.Oxidative phosphorylation: -Phosphorylation (synt of ATP from ADP) -Mitochondria -Coupled w/ ETC #Chemoosmotic hypothesis= -H+ pumped from respiratory chain à against conc. gradient across inner mitochondrial membrane à results in high electrical gradient à used in synth of ATP -Using a complex (ATP synthase = complex V) -3ATP/NADH -2ATP/FADH2 #ATP synthase rotary engine= -Machine -Allows H+ flow down electrical gradient -Rotation motion binds ADP to Pi groups to form ATP = ADP+PIàATP.

31.14.Hormones-function, structure: -Chemical signal molecules (in multicellular organisms) -Regulation of physio activity & maintain hemeostatis -Synthesized & secreted by signalling cells à target cells -Classified into 3 types based on action distance (Edocrine, Paracrine, Autocrine), #Endocrine (high distance, blood): -Secretes signal molecules to blood onto target cells #Endocrine organs: -Pancreas (insulin, glucagon) -Pituitary (growth hormone) -Thyroid&Parathyroid (thyroxine, parathyroid hormone) -Adrenals (cortex=cortisol, medulla=epinephrine) #Paracrine (close cells, in one tissue): only target cells close to the cell where its secreted from = neurotransmitters #Autocrine (one cell): cell responds to molecule of its own. #Classification according structure: -Peptide hormones (insulin, glucagon) = hydrophilic -AA derivatives (epinephrine, nor, thyroxine) = hydrophobic&hydrophilic -Steroid hormones (cortisol, aldosterone, proges) =hydrophobic.

32.15.Hydrophilic Hormones -Protein hormones -Receptors on the surface of target cells -Hormones outside the cell=1^st messenger, on the cell=2^nd messenger -G-protein on surface next to enzyme that converts ATPàcAMP #Ligand binds to receptorà conformation changeà Activation of effector system à inc. in conc. of 2^nd messenger (cAMP)à activation of protein kinase (signal amplification)à cell response. #Receptors (Insulin type1, Ion channel, G-protein) #Effector sys (Adenylate cyclase) #2^nd messengers (cAMP, Ca2+, IP3/DAG) (2^nd messenger)=change the enzymatic activity in a cell to cause the target cell response.

33.16.Lipophilic Hormones:- -Lipid soluble -Diffuse across plasma membrane & interact w/ intracellular receptors in cytosol or nucleus -Steroid / thyroid hormones = Hormone receptor in nucleus binds to hormone à hormone receptor complex binds to DNA (HRE) hormone responsive element à translation in cytoplasmà protein à cell response = Gene activation by hormone.

34.17.Neurotransmitters: -Chemical messengers -Transmitting signals from neuron to target across a synapse -Stored in vesicels (pre-synaptic vesicles) #Neurotransmitters types = 1. Biogenic amines (epinephrine, dopamine, serotonin(excitory), histamine) 2. AA (GABA=inhibitory, glutamate=excitory, glycine=inhibitory) 3. Acetylcholine (excitory) #Types of receptors: a) Ionotropic (ligand-activated ion channels) -excitory or inhibitory -ex: nicotinic acetylcholine receptors, serotionin. b) Metabotropic= involves 2^nd messengers pathway (G-protein) -excitory or inhibit -ex: most biogenic amines, all neuro peptide receptors. #Synaptic signal transmittion = action potential at nerve terminalàpresynaptic vesicle opens Ca2+ voltage-gatesà exocytosis of vesicles w/ neurotransm à synaptic cleft àbinding to specific receptor in post synapticà response

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