UWorld Metabolic Reactions

The Citric Acid Cycle (Oxidative Steps)

There are four oxidative steps in the citric acid cycle.

1) Isocitrate → α-Ketoglutarate (NAD+ to NADH) (reduced electron carrier)

2) a-ketoglutarate → succinyl-CoA (NAD+ to NADH) (reduced electron carrier)

3) Succinate → Fumarate (FAD to FADH2) (reduced electron carrier)

4) Malate → Oxaloacetate (NAD+ to NADH) (reduced electron carrier)

Succinyl CoA → Succinate

GDP + Pi → GTP

Transport Proteins

Facilitate movement of molecules across membranes. They may transport more than one type of molecule if the molecules have similar properties. Similar molecules compete for interactions with a transport protein.

Passive and Active Transport

Molecules may travel down their concentration gradient (passive transport/no energy required) and against their concentration gradient (active transport/energy required)

Uniport/Symport/Antiport

Transport proteins facilitate uniport if they transport one molecule, symport if the transfer two molecules in the same direction, and antiport if they transport two molecules in opposite directions.

Beta Oxidation

Involves the degradation of fatty acids to produce NADH and FADH2 which enters ETC used to reduce oxygen to water. Beta oxidation of fatty acids occurs in the mitochondria of eukaryotic cells and produces Acetyl CoA. L carnitine is required for fatty acids to enter the mitochondria.

Acetyl Coa Molecule Structure

Ketone ( O=) to S-CoA

Metabolic Pathways that occur in the Cytosol

Glycolysis intermediates, citrate, pyruvate… etc

Fermentation

The reduction of pyruvate to generate NAD+ for continued glycolysis under anaerobic conditions. Fermentation is carried out by the conversion of pyruvate to lactate.

Glycogen

Serves as a form of energy storage in tissues, muscle, liver, and in glial cells

Glycogenolysis

The degradation of glycogen into glucose and G6P units.The G6P units generated by glycogenolysis may enter other metabolic pathways like glycolysis and fermentation.

Glycogenolysis (Steps)

Glucose → Glucose 1 Phosphate → Glucose 6 Phosphate →

Phosphorolysis

Glycogen is primarily composed of several glucose units bound together by alpha 1-4 glycosidic linkages. Glycogen is cleaved into glucose 1 phosphate subunits by glycogen phosphorylase in a phosphorolysis reaction. Phosphorolysis breaks bonds by adding an inorganic phosphate group across them.

Decarboxylation Reactions (Citric Acid Cycle)

In the mitochondria, pyruvate undergoes three decarboxylation reactions as it is converted to Acetyl CoA and enters the citric acid cycle. The metabolic fate of carbon atoms in pyruvate precursors is mostly released as CO2.

NADH and FADH2

For each pair of electrons donated to the electron transport chain by NADH and FADH2, one oxygen atom is consumed during the reduction of O2 and H2O. NADH yields more efficient ATP synthesis than FADH2.

PDHC Pyruvate Dehydrogenase Complex

An enzyme that catalyzes the oxidative decarboxylation of pyruvate to form Acetyl CoA and NAD+ to form NADH. The PDHC requires lipoic acid for activity.

Oxidative Phosphorylation

is driven by NADH and FADH2. These molecules enter the electron transport chain and go through a series of favorable redox reactions that pump protons (H+) from the mitochondrial matrix and into the intermembrane space, creating electrochemical gradient that drives ATP synthesis (phosphorylates ADP → ATP)

The Electron Transport Chain

NADH and FADH2 enter the electron transport chain through redox reactions that have O2 as the final electron acceptor. These reactions occur in the transmembrane complexes that reside between the mitochondrial matrix and the intermembrane space.

Cytosol occurring metabolic processes

Glycolysis and pentose phosphate pathway.

Mitochondria occurring metabolic processes

Citric acid cycle and fatty acid oxidation

N Terminal Peptide Sequences

In eukaryotes, different metabolic pathways occur in different subcellular components. The enzymes required for each pathway must move to the appropriate component and N terminal peptide sequences direct them to their destination. Proteins that colocalize with one another are in the same compartment.

Nuclear Localization Sequences

Signal for the transport of proteins such as transcription factors to the nucleus.

Polyubiquitin Tags

Target defective/unnecessary proteins for destruction by a proteasome.

N Linked Carbohydrate

Chains are added to certain asparagine residues of proteins in the endoplasmic reticulum.

Transamination

How alpha-keto derivatives of amino acids are formed during which the amino group is transferred to alpha-ketoglutarate to form glutamate and keto acid. Keto acid goes through oxidative pathway to make Acetyl CoA or citric acid cycle intermediates.

Insulin Resistance

Insulin increases glucose uptake by cells. Cells that are overexposed to insulin can develop resistance and take up less glucose than they normally would in the presence of insulin.

No significant difference =

No change

Citric Acid Cycle Intermediates

Connor Is Kinky So She Fucks More Often

Citrate → Isocitrate → a-Ketoglutarate → Succinyl CoA → Succinate → Fumarate → Malate → Oxaloacetate (Enzyme named after intermediate pushes reaction)

Complex II (Electron Transport Chain)

The ETC depends on FADH and NADH2 to function. Complex II contains FAD/Succinate Dehydrogenase so it is part of the citric acid cycle and ETC as it oxidizes succinate to turn FAD to FADH2. FADH2 is then oxidized back to FAD+ to produce ubiquinol/

Complex I

Consumes NADH

Stereospecific Reactions in the Citric Acid Cyc

The conversion of citrate (achiral) into isocitrate (chiral) by aconitase and the transformation of fumarate to L malate in hydration reaction.

Enzymes involved in glycogenolysis

Glycogen phosphorylase catalyzes the release of glucose residues from linear glycogen segments debranching enzyme linearizes branched segments

Pyruvate Molecule

Pyruvate has 3 carbons, Acetyl CoA has 2, Cirtate and Isocitrate 4, A ketoglutarate 5, and everything else 6

Electron Transport Chain

Complexes I and II pass electrons NADH and FADH2 to ubiquinone (UQ), producing Ubiquinol (UQH2). In complex III UQH2 passes electrons to oxidized cytochrome C to make reduced Cytochrome C. Then in complex IV passes its electrons to oxygen to make water and oxidized cytochrome C.

ATP Synthesis

ATP synthesis is driven by protons crossing the inner mitochondrial membrane through ATP synthase. When protons are transported across the membrane by means that bypass ATP synthase, the energy released in this process cannot make ATP. This is decoupling because proton transfer is not coupled to ATP synthesis.

Fatty Acids

Fatty acids can be oxidized to form acetyl CoA and those with an even number of carbons produce half as many acetyl CoA molecules as they have carbons. Odd number fatty acids produce propionyl-CoA and Acetyl CoA. Unsaturated fatty acids require isomerization reactions to convert cis bonds to trans bonds, saturated fatty acids do not.

Pentose Phosphate Pathway

Generates ribose 5 phosphate and NADPH. The NADPH is generated by the reduction of NADP+ which is catalyzed by the oxidoreductase glucose 6 phosphate dehydrogenase and 6 phosphogluconate dehydrogenase

Reversible Reactions

The enzyme catalyzes/decreases the activation energy of both the forward and reversible reactions.

Irreversible Reactions

The reverse reaction cannot occur and converts the product of an irreversible reaction back to its precursor which requires a bypass reaction.

Glycolysis vs. Gluconeogenesis

Opposing metabolic pathways like Glycolysis and Gluconeogenesis use the same enzymes for reversible reactions (going in opposite directions) but must use different enzymes to catalyze distinct reactions for irreversible steps.

Catabolic Pathways

Catabolic pathways degrade complex molecules into simpler molecules to produce high energy nucleotide triphosphates. NTPs provide energy for muscle contraction.

Anabolic Pathways

Use simpler molecules (amino acids, sugars) as precursors to synthesize more complex molecules (proteins, polysaccharides). Anabolism requires energy from NTPs and are usually paired with catabolism.

Net NTP Production

The difference between the numbers of NTPs (ATP, GTP, etc) produced and consumed in a process. (total consumed NTPs - total produced NTPs)

Cori Cycle

Pyruvate is reduced to lactate to make NAD+ during exercise. Lactate that builds up in muscles is sent to the liver where it is converted back to glucose and returned to the muscles. 8 total NTPs are consumed in this cycle. (2 from glycolysis and 6 from gluconeogenesis). Glycolysis (catabolic process) and gluconeogenesis (anabolic process) are connected by cori cycle.

Gluconeogenesis and Fatty Acid Oxidation

Gluconeogenesis is an anabolic process that requires energy input from ATP equivalents. The necessary energy is provided by fatty acid oxidation (catabolic process). Fatty acid degradation of Acetyl CoA yields NADH and FADH2 which can enter the ETC to produce ATP.

PFK-1 (Phosphofructokinase-1)

The rate of glycolysis is controlled by PFK-1 which is stimulated by the allosteric effector F2, 6BP. When glycolysis is active F2, 6BP is also most likely active.

Pathways for low Blood Glucose

When blood glucose is low, the pancreas releases glucagon, which stimulates gluconeogenesis and glycogenolysis to release glucose from the liver into the bloodstream while decreasing glycolysis.

Oxidative Stress

Occurs when cells have an overabundance of reactive oxygen species (ROS) which cause damage when they react with other membranes and molecules. The ETC produces ROS when it fails to fully reduce water.

Apoptosis

Programmed cell death caused by DNA damage or reactive oxygen species. It is activated when cytochrome C is allowed to leave the mitochondria and enters the the cytosol to activate caspase. Caspase activates degradive pathways like proteolysis.

ATP yield of oxidative phosphorylation

Directly proportional to the number of FADH and NADH2 molecules that enter the ETC

1.5 ATP per FADH and 2.5 ATP per NADH so multiply the number given by this for ATP

Complex V

Complex V activity depends on proton availability. Proton concentration in the intermembrane space can be increased by increasing the number of NADH molecules that enter the ETC. NADH from glycolysis can indirectly enter the mitochondrial matrix by first passing its electrons to oxaloacetate to form malate.

Decoupling

When one chemical process provides the energy for another, the processes are said to be coupled. Decoupling two processes causes the energy providing step to continue without driving the dependent process.

Irreversible Steps of the Citric Acid Cycle

The irreversible steps regulate the citric acid cycle. These steps are catalyzed by the enzymes citrate synthase, isocitrate dehydrogenase, and a ketogluterate dehydrogenase. These enzymes are inhibited by NADH, ATP, citrate, and succinyl-CoA and activated by ADP and calcium. These enzymes are not under hormonal control.

Complex II Succinate-Ubiquinone Reductase.Succinate Dehydrogenase

Oxidizes succinate to fumarate and transfers electrons to Complex III. Electrons are transferred from FADH2 to iron sulfur centers in complex II, then to ubiquinone/coenzyme Q which goes to complex III as ubiquinol.

Proton Gradient

The ETC in the inner mitochondrial membrane generates the proton gradient required for ATP synthesis to occur.

Electron Transfer (Reduction Potential)

Reduction potential indicates an oxidized molecule’s affinity for electron, electrons are transferred from species with lower reduction potential (less affinity) to species with higher reduction potential (more affinity for electrons) throughout the ETC.

Futile Cycle

When anabolic and catabolic lipid metabolism occur at the same rate simultaneously, fatty acids are built up and then broken down, leading to wasted energy with no gain so a futile cycle.

A decrease in catabolism:

Indicates that the metabolic equilibrium has shifted towards anabolism and fatty acids are not being broken down to make energy.

A decrease in anabolism:

Indicates that the metabolic equilibrium has shifted towards catabolism and fatty acids are being broken down to make energy.

CPTI Carnitine Palmitoyltranfserase I

The rate limiting step of fatty acid oxidation. A molecule that targets and inhibits fatty acid oxidation enzymes and would likely target CPTI as well.

Catabolic Hormones

Hormones that stimulate catabolic processes (fatty acid oxidation) (Examples of hormones: (glucagon, epinephrine, and cortisol: all stimulate fatty acid oxidation)

Anabolic Hormones

Hormones that stimulate anabolic processes and inhibit catabolic processes (fatty acid oxidation). Insulin is an anabolic hormone and stops fatty acid oxidation.

Beta Oxidation (Steps)

Fatty Acyl CoA molecules are broken down two carbons a time to form Acetyl CoA

1. Oxidation of Acyl CoA by the enzymes Acyl Dehydrogenase forming alpha, beta - unsaturated trans enoyl CoA. FAD as an oxidizing agent is reduced to FADH2.

2. Hydration of the double bond by the enzyme enoyl CoA hydratase, The hydration reaction adds a hydroxyl group to C3, to form beta-hydroxyaxyl CoA

3. Oxidation of the hydroxyl group by beta hydroxyacyl CoA dehydrogenase to form acetoacyl CoA which can be a precursor molecule for ketone body and cholesterol synthesis.

4. Acetyl CoA acyltransferase forms acetyl CoA.

Acetyl CoA Carboxylase (ACC)

An enzyme of fatty acid synthesis but also regulates fatty acid oxidation through its product malonyl CoA. Dephosphorylated ACC stimulates synthesis and inhibits oxidation whereas phosphorylated ACC inhibits synthesis and promotes oxidation.

a-, B-, and y phosphates

The 3 phosphate groups on an NTP are designated a-, B-, and y phosphates. The a phosphate is linked to the nucleoside and the y phosphate is farthest away from the nucleoside and leaves in most reactions. NTP cleavage releases y phosphate as inorganic Phosphate Pi, or the y and B phosphates as pyrophosphate.

Glycogen is composed of:

glucosyl residues linked by a (1 → 4) glycosidic bonds in linear segments and a (1 → 6) glycosidic bonds at branch points. (The O-O carbon connecting the Os is the carbon 1 )

In glycolysis 1 glucose molecule produces:

1 glucose molecule creates 2 pyruvate, 2 ATP molecules, and 2 NADH molecules. When glucose 6 phosphate enters glycolysis less ATP is consumed.

Skeletal Muscle and Liver (Glycogen)

Skeletal muscle and liver are the major sites of glycogen sotrage in the body. The activity of glucose 6 phosphatase allows the liver to release glucose derived from glycogenolysis and gluconeogenesis into the blood wheras muscle lacks significant levels of gloucose 6 phosphatase. Liver releases more glucose into blood.

Reversible Reaction. G = 0

Reactions that operate near equilibirum are reversible and can move forward or backwards.

Irreversible Reaction (G = -)

Reactions that operate far from equilibrium are irreversible and only move in one direction.

Gluconeogenesis

Glucose is synthesized from pyruvate and lactate through gluconeogenesis. Glucogenesis shares enzymes with glycolysis.

Lactate Dehydrogenase

Uses pyruvate to oxidize NADH, producing lactate and NAD+ in a process called fermentation

Pyruvate Kinase is not used in:

Gluconeogenesis

Electron Transport Chain (ETC)

A series of protein complexes in the inner mitochondrial membrane that couples the movement of electrons through a series of redox reactions to pump protons across the membrane to form a protein gradient that makes ATP during cellular respiration.

4 Complexes of Electron Transport Chain

Complex 1) Receives a pair of electrons from NADH to reduce ubiquinone to ubiquinol.

Complex 2) Receives a pair of electrons from FADH to reduce ubiquinone to ubiquinol

Complex 3) Ubiquinol from complex 1 and 2 transfers electrons to cytochrome C. One pair of electron reduces 2 cytochrome c.

Complex 4) Receives electrons from cytochrome c and transfers them to molecular oxygen (O2). Four electrons fully reduce an oxygen so 2 electrons reduce half of O2 to make H2O.

ATP Hydrolysis

When water is added to a bond linking two phosphate groups in an ATP molecule to make ADP and Pi (inorganic phosphate). This is exothermic (negative delta H) and uses heat. It is used to drive energetically unfavorable reactions.

Bond Cleavage is always:

Endothermic

Bond formation is always:

Exothermic

Branching glucose residues in glycogen are linked via:

alpha (1-6) glycosidic bonds ; the other glucose residues are linked by alpha (1-4) glycosidic bonds

Liver Glycogenolysis (Steps)

1. Phosphorylase (releases glucose 1 phosphate from linear regions)

2. Debranching Enzyme (Transfers/removes 4 branch residues)

3. Phosphorylase (Release remaining linear regions)

4. Phosphoglucomutase ( Converts G1P to G6P )

5. Glucose 6 Phosphatase (Dephosphorylates G6P)

Glucagon binding to its receptor stimulates: (Glycogen)

The release of phosphorylated glucose from glycogen in liver cells

Allosteric Modulators

Influence enzyme function by binding reversibly to sites other than the active site through noncovalent interactions.

NADH or FADH2 produced in glycolysis and the citric acid cycle feed into the:

Electron Transport Chain (ETC) to make ATP

NADPH

NADPH is a reducing agent used in various bio pathways. The primary cystolic source of NADPH is the oxidative phase of the pentose phosphate pathway.

Oxidative Phase of the Pentose Phosphate Pathway

2 molecules of NADPH are produced as glucose 6 phosphate is oxidatively decarboxylated to a pentose phosphate.

Fasting State

Ketone bodies are produced in a fasting state. In the fasting state, glucagon signals the phosphorylation and regulation of various enzymes to increase the production of glucose through glycolgenolysis and gluconeogenesis.

NAD+

Glycolysis consumes 2 NAD+ to produce 2 NADH and 2 Pyruvate; An additional 2 NAD+ are required to convert the pyruvates to 2 acetyl-CoA

Equilibrium Arrows (Biochemistry)

Many pathways contain multiple reactions at equlibrium and involve metabolites that are shared between pathways. If one pathway is effected there may be a shift in the equilibrium.

Gluconeogenic Precursors

Gluconeogenesis synthesizes glucose from noncarbohydrate molecules to meet the body’s glucose needs when dietary or stored carbohydrates are insufficient. Lactate, pyruvate, and glycerol are the gluconeogenic precursors as are amino acids.

Inborn Errors of Metabolism

Inborn Errors of Metabolism are genetic disorders that impair metabolic pathways. These disorders are treated by supplementing a deficient enzyme with a functional version or by providing an alternate source of metabolic product that follows a separate pathway.

Fatty Acid Synthesis

Fatty Acid Synthesis is the process of linking acetyl CoA units together and reducing carbonyls to the alkyl form. To synthesize a fatty acid containing 2n + 2 carbons, n ATP molecules and n NADPH molecules must be consumed to form ADP and NADP+

The Pentose Phosphate Pathway

The pentose phosphate pathway produces ribose 5 phosphate by decarboxylation of G6P (oxidative phase) or by rearranging the carbon atoms in F6P first and then glyceraldehyde 3 phosphate (non oxidative phase). F6P can enter both phases.

Glycolysis produces the most:

ATP of any metabolic pathway. The enzymes of glycolysis are most important for cells lacking ATP.

Glycogenolysis (Glycogen Degradation)

Epeniphrine binds to G coupled receptors and activate adenylate cyclase which converts ATP to cAMP which allosterically activates protein kinase A to activate glycogen phosphorylase, the first enzyme in glycogenolysis.

Glycogenesis (Glycogen Synthesis)

Is induced by insulin in response to high glucose levels.

a ( 1 → 6 ) Linkages (Glycogen)

Are facilitated by the glycogen branching enzyme

a ( 1 → 4 ) Linkages (Glycogen)

Are facilitated by glycogen synthase

Glycogen Phosphorylase

Glycogen is degraded by phosphorylsis/the addition of a phosphate to break a bond to produce glucose 1 phosphate G1P. The G1P glycogen phosphorylase makes can be transformed to G6P for glycolysis or the pentose phosphate pathway.

Fasting (Glucose Consumption)

In the early stages of fasting the liver degrades glycogen (glycogenolysis) prolonged fasting synthesizes glucose (gluconeogenesis)

Pyruvate Carboxylase

The first unique irreversible step to gluconeogenesis.

Pyruvate → (Pyruvate Carboxylase) Oxaloacetate → (Gluconeogenesis) → Glucose