Fatty Acid Metabolism

Fatty Acid Metabolism

• Fats are efficient for long-term energy storage because they are highly reduced and not solvated
• Dietary fats are emulsified by bile salts and broken down by lipases
• The resulting products are reassembled into triacylglycerols (TAGs)
• TAGs are then delivered in chylomicrons
• Glucagon activates hormone-sensitive lipase that mobilizes stored fat
• Fatty acids are activated for breakdown by fatty acyl-CoA synthetase with ATP
• This activation results in the formation of fatty acyl-CoA
• Carnitine is required for fatty acids to cross the mitochondrial membrane
• Beta oxidation is a stepwise redox process that breaks down fatty acids at the beta-carbon
• Beta oxidation produces NADH, FADH2, and acetyl-CoA.
• Oxaloacetate depletion during gluconeogenesis limits the citric acid cycle
• Excess acetyl-CoA is converted into ketone bodies
• An overproduction of ketone bodies can lead to ketoacidosis
• Acetyl-CoA carboxylase (ACC) converts acetyl-CoA into malonyl-CoA
• This conversion commits acetyl-CoA to fatty acid biosynthesis
• Acyl carrier protein (ACP) is used instead of CoA in fatty acid biosynthesis
• Fatty acid synthase catalyzes step-by-step reductions of the beta carbon
• Citrate transports acetyl-CoA equivalents across the mitochondrial membrane for biosynthesis
• AMP-dependent kinase regulates ACC and is identified as a potential drug target for obesity
• Dietary fats are emulsified, digested, and repackaged before entering lymphatic circulation, rather than direct absorption by intestinal cells
• Acyl Carrier Protein (ACP) is the "handle" used for fatty-acid biosynthesis
• The redox series steps of a fatty-acid beta-carbon during lipogenesis are Reduction → Dehydration → Reduction
• Fatty acid activation is the attachment of coenzyme A to a fatty acid for catabolism
• Carnitine is an amino acid derivative that is used for fatty-acid translocation
• The redox series of a fatty-acid beta-carbon during beta oxidation is Oxidation → Hydration → Oxidation → Thiolysis
• Fat mobilization steps: Hormone (glucagon/epinephrine) → cAMP → PKA → hormone-sensitive lipase → TAG breakdown
• Potential drug targets for obesity that are being investigated: AMP-dependent kinase and acetyl-CoA carboxylase (ACC)
• Metabolizing the twenty-carbon fatty acid arachidonate yields 10 acetyl-CoA, 9 FADH2, and 9 NADH
• During fatty-acid biosynthesis, acetyl-carbons from acetyl-CoA cross the inner mitochondrial membrane as citrate

Protein Catabolism

• Proteins are denatured in the stomach, digested in the intestine, and amino acids are absorbed
• Dietary amino acids mainly replenish amino acids lost during protein turnover
• Protein degradation is regulated by the ubiquitin-proteasome system
• Protein deficiency or malnourishment may result in a negative nitrogen balance
• The excess nitrogen in positive nitrogen balance is excreted as urea
• Aminotransferase reactions are central to amino acid catabolism
• Glutamate is a central molecule in nitrogen metabolism
• Glutamate can be directly deaminated
• Carbamoyl phosphate is produced from ammonia from deamination
• The urea cycle combines ammonia, from carbamoyl phosphate, and aspartate to create urea
• Amino acid carbon skeletons can be glucogenic or ketogenic
• Glutamate is converted to α-ketoglutarate, Aspartate is converted to oxaloacetate, and Alanine is converted to pyruvate
• Other amino acids are converted to CAC intermediates
• Methionine to SAM (S-adenosyl methionine) acts as a major methyl donor
• Phenylalanine to tyrosine occurs unless an enzyme is defective, which results in PKU
• The macromolecule made with amino acids from dietary protein is protein
• The ubiquitin-proteasome system is the molecular process that allows for protein turnover
• Methionine is the amino acid in whose catabolic pathway the methyl donor, abbreviated SAM, is made
• Phenylalanine is the amino acid substrate of the enzyme encoded by the gene that is mutated in the genetic disorder PKU
• Surplus nitrogen in a state of positive nitrogen balance is excreted as urea
• Digestion of the peptide bonds in dietary proteins starts in the stomach
• An acetyl group from acetyl-CoA connot contribute to carbamoyl phosphate
• Protein deficient or calorie-only malnutrition can cause protein deficiency disease
• Carbamoyl phosphate feeds into the urea cycle and pyrimidine synthesis
• Phenylalanine, Isoleucine, Threonine, Tryptophan, and Tyrosine: are the amino acids that can be made into glucose and acetyl-CoA

Amino Acid Anabolism

• Animals obtain nitrogen from dietary proteins
• Plants can use ammonia, while some bacteria fix N₂
• Nitrogen fixation via nitrogenase and nitrogenase reductase is sensitive to oxygen
• Glutamate is created by glutamate dehydrogenase
• Glutamine is created by glutamine synthetase
• Pyruvate, oxaloacetate, and α-ketoglutarate yields alanine, aspartate, and glutamate
• Other amino acids are created from energy metabolism intermediates
• Essential amino acids require longer synthetic pathways
• Aminotransfer describes a core biosynthetic reaction
• Amino acids yield biogenic amines through decarboxylation
• Glycine plus intermediates yields heme
• Heme yields bilirubin (a bilin), which is excreted in bile
• Tryptophan requires the longest anabolic pathway
• Jaundice results from heme catabolism, due to the accumulation of bilirubin
• The anabolism of all amino acids fails to require acetyl-CoA
• The anabolism of heme begins with glycine and succinyl-CoA, then goes to ALA, then porphobilinogen, then protoporphyrin IX, then heme (with Fe²⁺)

Metabolism Overview

• Metabolism functions to provide energy and building blocks for cellular processes
• Adenosine Triphosphate (ATP) acts as the energy currency by storing and transferring energy to drive cellular work
• Catabolism breaks down molecules and releases energy, while anabolism synthesizes biomolecules and requires energy
• B-complex vitamins serve as cofactors in metabolic reactions
• Enzymes regulate reactions in metabolism in order to avoid metabolic equilibrium and maintain energy flow
• Metabolic pathways take place in unique cellular locations to regulate metabolic flux
• Unfavorable reactions are coupled with favorable reactions (e.g., ATP hydrolysis)
• Electron carriers such as NAD⁺ and FAD are involved in redox reactions
• Acetyl-CoA serves as a central metabolic intermediate, essential for both energy production and biosynthesis
• Metabolic pathways adjust constantly to energy and material demands
• The majority of metabolism is to provide cellular energy
• B-complex vitamins function as coenzymes
• ATP is the energy currency of cells because it powers almost all cellular work
• Metabolism encompasses the catabolic degradation of complex dietary compounds
• Some metabolism involves materials in our diet that we build ourselves from
• Compartmentalization, enzyme regulation, and coupling reactions are needed to avoid equilibrium in overall energy metabolism
• Anabolic biosynthesis of complex biomolecules are involved
• Metabolic pathways provide energy and building blocks for all life processes
• Anabolic pathways use energy and building blocks to make and do things
• Enzymes make unfavorable reactions take place spontaneously by coupling them with favorable reactions, like ATP hydrolysis
• Dinucleotides NAD and FAD are used in redox reactions
• Acetyl-CoA describes the “central compound of energy metabolism"
• True, the use of metabolism is to provide energy for doing unfavorable things
• Metabolism involves "stuff", the stuff to build with and the stuff that's made
• Catabolic pathways release energy and provide building blocks
• Equilibrium of energy metabolism is avoided by enzyme regulation and substrate flux
• Coenzyme A, NAD⁺, and FAD contain a B vitamin and an adenosine nucleotide

Oxidative Phosphorylation

• The electron transport chain (ETC) is a series of protein complexes
• The ETC's protein complexes transfer electrons to oxygen, generating a proton gradient
• The proton gradient in the ETC powers ATP synthesis
• The proton gradient can generate heat via uncoupling proteins
• Complexes I-IV in the ETC transfer electrons from NADH and FADH₂ to oxygen while pumping protons
• Ubiquinone (Q) and cytochrome c are electron carriers in the ETC that shuttle electrons between complexes
• The Q cycle is a mechanism in Complex III that enables electron transfer from ubiquinone to cytochrome c
• The chemiosmotic hypothesis: ATP is produced when protons travel back into the mitochondrial matrix through ATP synthase
• ATP synthase (F₁F₀ Complex): a rotary motor enzyme that produces ATP through the proton gradient
• Coupling the proton gradient to ATP synthesis: the proton-motive force powers ATP production through oxidative phosphorylation
• Proteins allowing proton leakage reduce ATP production and generate heat
• Oxygen serves as the final electron acceptor, receiving electrons and protons to produce water
• Compare function and electron donors/acceptors between ETC Complexes I-IV for their differences
• Ionophores and ETC disruptors dissipate the proton gradient, uncoupling ATP synthesis
• Compare mitochondrial and chloroplast ATP synthases similarities and differences in oxidative phosphorylation and photosynthesis
• ETC proteins provide insights into evolutionary relationships among organisms
• Gradient-driven rotary motors harness energy from gradients to power molecular machines
• The biggest difference between Complex II and other ETC complexes: Complex II fails to pump protons
• The proton gradient provides the energy for oxidative phosphorylation of ATP
• The ETC-created proton gradients drives ATP synthesis via chemiosmosis
• NADH, FADH2, ubiquinone (Q), and cytochrome c are electron carriers utilized in the ETC
• The coupling of proton gradient to oxidative phosphorylation by the ETC is Chemiosmotic coupling
• Uncoupling proteins can generate heat in the proton gradient
• Complex II does not interact with any diffusible electron carrier
• The chemiosmotic model proposes that a proton gradient across the inner mitochondrial membrane powers ATP synthesis.
• Complex III receives electrons from a lipid-soluble electron carrier and transfers them to a water-soluble protein using the Q cycle
• An electron will go through 3 complexes and 2 diffusible carriers once in the ETC before being dumped to oxygen
• Cytochrome c was important in providing support for evolutionary tree of life.
• The chemiosmotic hypothesis explains how the proton gradient is usually used
• ADP, ATP, phosphate, pyruvate, and other small metabolites are the compounds with transporters in the inner mitochondrial membrane
• Light reactions of photosynthesis, and mitochondrial electron transport chain and oxidative phosphorylation share use use of an electron transport chain to generate a proton gradient that drives ATP synthesis
• Cytochrome b6f complex is a multi-electron-carrier complex in the the electron transport chain of photosynthesis
• Both Complex III and Complex IV of the ETC pump protons and contain cytochromes
• The F1F0 ATP synthase and chloroplast ATP synthase are structurally and functionally homologous, both using a proton gradient to synthesize ATP
• In the waterwheel analogy, the proton pumps which are Complexes I, III, IV of the ETC are like paddles making them more efficient
• Ubiquinone (Q), cytochrome c, NADH, and FADH2 are the important carriers in the ETC
• Complex I takes electrons from NADH and gives them to ubiquinone (Q)
• The role of Complex IV in the electron transport chain is to transfer electrons to oxygen to form water and pumps protons
• Ionophore: facilitates ion transport across membranes and disrupts ion gradients
• The F1F0 ATP synthase is a rotary motor that synthesizes ATP using proton gradient energy
• Energy from the proton gradient can be used in a number of different ways
• The F1F0 ATP synthase is an example of a gradient-driven rotary motor
• Complex I pumps protons and uses NADH, unlike Complex II which uses FADH2 and does not pump protons
• Protein chemists and evolutionary biologists are greatly indebted to Cytochrome c.
• An uncoupling protein is a protein that allows protons to bypass ATP synthase, dissipating the gradient as heat