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Catabolism

Degradation from large complex molecules to smaller simple ones:
1) Carbohydrate Catabolism:
a) Glycolysis
b) Penthose Phosphate Passway
c) Kerbs Cycle (Cytric Acid Cycle)
d) Electron transport Chain
e) Glycogenolysis
2) Lipid Catabolism
a) β oxidation
b) Ketone metabolism
c) Cholestrol catabolism
3) Protein Catabolism
4) Nucleic Acid Catabolism

Glycolysis: Definition and Enzymes

Converts Glucose to Pyruvate (or Lactate in anaerobic conditions)

Net energy yield: 2 ATP, 2 NADH

Steps:
1) Glucose ---> Glucose-6p
2) Glucose-6p <---> Fructose-6p
3) Fructose-6p ---> Fruktose-1,6 bisphosphate ---
4) Fruktose-1,6 bisphosphate <--->Glyceraldehyde-3p + DHAP
4-a) Glyceraldehyde-3p <---> DHAP
5) Glyceraldehyde-3p <---> 1,3-Biphosphoglycerate
6) 1,3-Biphosphoglycerate <---> 3-Phosphoglycerate
7) 3-Phosphoglycerate <---> 2-Phosphoglycerate
8) 2-Phosphoglycerate ----> Phosphoenylpyruvate (PEP)
9) PEP ---> Pyruvate

Enzymes: 1) Hexokonase (Glucokinase in liver), 2) Glucose 6-p isomerase (Phosphoglucose isomerase)
3) PFK, 4) Aldolase, 4-a) Triose-phosphate isomerase, 5) Glyceraldehyde-phosphate dehydrogenase, 6) Phosphoglycerate kinase, 7) Phosphoglycerate mutase, 8) Enolase, 9) Pyruvate Kinase

Hexokinase, PFK and Pyruvate Kinase are irreversible and regulatory

PFK is Rate Limiting Step

ATP is used in steps 1 & 3
NADH produced in 5
ATP produced in 6 & 9

Glycolysis: regulators

1) Hexokinase inhibited by:G6P
(In Liver: Glucokinase regulated by: Glucokinase regulatory protein: GKRP)

2) PFK-1 Stimulated by AMP & Fructose-2,6-bisphosphate⁰ and inhibited by ATP & Citrate
PFK-2 stimulated by Insukine and inhibited by Glucagon

3) Pyruvate kinase activated by: fructose-1,6-bisphosphate and Insuline⁰, Inhibited by ATP, Acetyl-CoA, Glucagon⁰ and Alanine⁰

⁰Liver specific

Endocrine regulation of Glycolysis?

Insulin stimulates
Glucagon Inhibits
Epinephrin stimulates in muscles and inhibits in liver

Glucose-1-Phosphate

In glycogenolysis, it is the direct product of the reaction in which Glycogen Phosphorylase cleaves off a molecule of glucose from a greater glycogen structure.

Also comes from Galactose-1p via Galactose-1p uridyltransferase.

To be utilized in cellular catabolism it must first be converted to glucose 6-phosphate by the enzyme Phosphoglucomutase.

Phosphoglucomutase

Converts Glucose-1-Phosphate to Glucose-6-Phosphate

Substrate-level Phosphorylation

Type of chemical reaction that results in the formation of ATP by the direct transfer and donation of a phosphoryl (PO3) group to ADP from a reactive intermediate:
ADP+Pi -----> ATP
Glycolysis: 2ATP per Glucose
TCA (Kerb's) Cycle: 2ATP per Glucose

Mitochondrial Shuttle

The mitochondrial shuttles are systems used to transport reducing agents across the inner mitochondrial membrane.

NADH cannot cross the inner mitochondrial membrane, but it can reduce another molecule that can cross the membrane, so that its electrons can reach the electron transport chain.

1) Malate-Spartate shuttle (max 34 ATP per Glucose)
2) Glycerol-Phosphate shuttle (max 32 ATP per Glucose)

Embden-Meyerhof Pathway?

Glycolysis (another name)

Not to be confused with:
Entner-Doudoroff (Bacterial metabolism: Glycolytic pathway in aerobic bacteria. There is no Entner-Doudroff pathway in Eukariots)

Rate Limitting Step

The rate-determining step (RDS) is a chemistry term for the slowest step in a chemical reaction.

The rate-determining step is often compared to the neck of a funnel; the rate at which water flows through the funnel is determined by the width of the neck, not by the speed at which water is poured in. In similar manner, the rate of reaction depends on the rate of the slowest step

Rate Limiting Step of Glycolysis

Phosphofruktokinase (PFK)
Conversion of Fructose-6-phosphate to Freuctose-1,6-bisphosphate

Enzyme for:
2-phosphoglycerate <---> Phosphoenolpyruvate (PEP)

Enolase

This enzyme is inhibited by Fluoride

Enzyme for:
PEP (Phosphoenolpyruvate) <--> Pyruvate

Pyruvate Kinase

It is a regulatory and irreversible step:
Stimulators +: Fructose-1,6p, Insuline⁰
Inhibitors: ATP, Acetyl-CoA, Alanine⁰, Glucagon⁰

⁰Liver specific

Lactic acid is converted back to Glucose via ----

Cori cycle

In Liver: Lactae --> Pyruvate ---> Glucose
Lactate dehydrogenase

Metabolic fates of Pyruvate?

1) Oxidative Decarboxylation by Piruvate Dehydrogenase to produce: Acetyl-CoA.
It is the link reaction between Glycolysis and kerb's Cycle and yields one NADH per Pyruvate (2 per glucose.)
Acetyl-CoA alternatively can be used for Fatty acid synthesis

2) Reduction by Lactate Dehydrogenase to produce Lactate in Anaerobic glycolysis


3) Carboxylation by Piruvate Carboxylase to produce Oxaloacetate, which is used for Gluconeogenesis, and also is a mediate for TCA cycle

4)Transamination by Alanine Transaminase to produce Alanine in Protein metabolism

Note: Oxaloacetate (C₄)

HMP Shunt?

Hexose Monophosphate Shunt or Pentose Phosphate Pathway (PPP)
Glucose-6P ---> Pentose + NADPH in Cytosol

Pentose = Ribose-5P (or Ribulose-5P) is used for nucleotid synth.
NADPH (Nicotinamide adenine dinucleotide phosphate) is used for Fatty acid and Steroid synth, and is Extremely Important for RBCs metabolism.

Lack of NADPH due to deficiency of the enzyme:
Glucose-6P dehydrogenase (G6PD) (Favism)
results in Hemolitic Anemia

Glucose-6p ---> 6-Phosphogluconolactone , via G6PD is the Rate Limiting Step in PPP

Cori Cycle

Metabolic pathway in which lactate produced by anaerobic glycolysis in the muscles moves to the liver and is converted to glucose, which then returns to the muscles and is converted back to lactate.

In Muscle: Glucose > Pyruvate > Lactate
In Liver: Lactate > Pyruvate > Glucose

Lactate dehydrogenase

Respiratory chain?

Electron Transport Chain
in: Inner Mitochondrial Membarane
Major source of ATP production: Oxidative Phosphorylation of ADP (32-34 ATP per glucose)

Cytochromes

Membrane-bound hemoproteins
Contain heme groups and carry out electron transport:
Redox reactions
In Mitochondrial inner membrane and Endoplasmic reticulum of eukaryotes


Due to the Heme molecule which contains a metal ion
(usually Fe), which interconverts between Fe2+ (reduced) and Fe3+ (oxidised) states, Cytochromes are capable of performing oxidation and reduction and beacause they are held within membranes in an organized way, the redox reactions are carried out in the proper sequence for maximum efficiency.

Redox reaction

Redox (shorthand for reduction-oxidation reaction) describes all chemical reactions in which atoms have their oxidation number (oxidation state) changed. This can be either a simple redox process, such as the oxidation of carbon to yield carbon dioxide (CO2) or the reduction of carbon by hydrogen to yield methane (CH4), or a complex process such as the oxidation of sugar(C6H12O6) in the human body through a series of complex electron transfer processes.

The term comes from the two concepts of reduction and oxidation. It can be explained in simple terms:

Oxidation = the loss of electrons or an increase in oxidation state by a molecule, atom, or ion.
Reduction = the gain of electrons or a decrease in oxidation state by a molecule, atom, or ion.

Note:
Loss of electron = Loss of H (Oxidation)
Gain of electron = Gain of H (reduction)

ATP production

A) Substrate-level phosphorylation:
1. Glycolysis
2. Kerb's Cycle (Citric acid cycle or TCA)

B) Oxidative Phosphorylation:
3. Electron Transport Chain (ETCor Respiratory chain)

Note:
1) in Cytosol, 2) in Mitocchondrial Matrix and 3) in Inner Mitochondrian Membrane

Acetyl-CoA is a metabolite of -----

Carbohydrates, Proteins and Lipids

Acetyl-CoA, Pyruvate and Glucose-6-phosphate are 3 Key Intermediates of Metabolism

Metabolic fates of Acetyl-CoA

1. Oxydation in Kerb's Cycle (GTP, NADH and FADH production)
2. Fatty acids (via Malonyl CoA)
3. HMG Co-A (3-hydroxy-3-methylglutaryl-coenzyme A), which is a precursor of Cholestrol and Ketone bodies.

Stoichiometry of Glycolysis

Glucose + 2Pi + 2ADP + 2NAD⁺ --> 2Pyruvate + 2ATP + 2NADH + 2H⁺ + 2H₂O

Stoichiometry of TCA (Citric Acid Cycle)

Acetyl-CoA + 3NAD⁺ + FAD + Pi + GDP + 2H₂O ---> 2CO₂ + 3NADH + FADH₂ + GTP + 2H⁺ + CoA

Important metabolites in Kerb's Cycle which provide substrates for biosynthetic processes

Cytrate ----> Fatty acids
α-Ketoglutarate ----> Non essential amino acids
Succinyl CoA ---> Heme
Oxaloacetate ---> Glucose

Carbon atom number change during Kerb's cycle?

Oxaloacetate (C₄) + Acetyl-CoA (C₂) --> Citrate (C₆)

Citrate (C₆), α-Ketoglutarate (C₅), Succinyl-CoA (C₄), Oxaloacetate (C₄)

Coenzymes of TCA cycle?

5 Coenzymes for 8 important reactions:
1) FAD
2) NAD⁺
3)Thiamine Pyrophosphate (TPP from Vit B₁)
4) Lipoic acid
5) Coenzyme A

TPP (Thiamine Pyrophosphate) a derivative of Thiamin (Vit B₁) works as a coenzyme in many enzymatic reactions, such as:
Pyruvate dehydrogenase complex
Pyruvate decarboxylase complex in ethanol fermentation
Alpha-ketoglutarate dehydrogenase complex
Branched-chain amino acid dehydrogenase complex
Transketolase (Ribose-5p --> Fructose-6p in PPP)

Lipoic acid is a coenzyme in:
Pyruvate dehydrogenase complex
Alpha-ketoglutarate dehydrogenase complex

Important irreversible regulatory enzymes of TCA cycle?

1. Citrate synthase: Inhibited by NADH
2. Isocitrate dehydrogenase: Inhibited by ATP and stimulated by ADP
3. α-Ketoglutarate dehydrogenase: Inhibited by NADH

The 2nd item is Rate Limiting Step in the cycle

Rate Limiting Step in Kerb's Cycle?

Isocitrate dehydrogenase (IDH):

It catalyzes the third step of the cycle: the oxidative decarboxylation of isocitrate, producing alpha-ketoglutarate (α-ketoglutarate) and CO2 while converting NAD+ to NADH.

This is a two-step process, which involves oxidation of isocitrate (a secondary alcohol) to oxalosuccinate (a ketone), followed by the decarboxylation of the carboxyl group beta to the ketone, forming alpha-ketoglutarate

How many ATP, NADH and FADH₂ per glucose are produced after Kerb's cycle?

3NADH, FADH₂ and ATP (GTP) per one Acetyl-CoA plus One NADH which is produced in Pyruvate decarboxylation (Link reaction between Glycolysis and Kerb's Cycle) results in: 4NADH + FADH₂+ ATP (GTP) per one Acetyl-CoA molecule.

Should be multiplied by 2 because there are 2 Piruvates and 2 Acetyl-CoA after Glycolysis:

Final result:
8 NADH
2FADH
2 ATP

Each NADH yields --- ATP and each FADH₂ yields --- ATP

3, 2

Coenzyme Q10

Also known as Ubiquinone, Ubidecarenone, Coenzyme Q, and abbreviated at times to CoQ10, CoQ, Q10, or Q
Cytochrome C Oxidoreductase (Cytochrome Reductase)
Cytochrome Complex III
Primarily in the mitochondria, a component of the electron transport chain, generating energy in the form of ATP

Those organs with the highest energy requirements—such as the heart, liver and kidney —have the highest CoQ10 concentrations.

The First Law of Thermodynamics

Law of Conservation of Energy.
This law states that energy cannot be created, nor can it be destroyed.
What is happening is transfer of energy from one form to another, or from one substance to another

The Second Law of Thermodynamics

The entropy of the universe is always increasing

The Second Law of Thermodynamics is the Law of Increasing Entropy.
a system will always want to move toward a lower energy state.

Gibbs Free Energy

Gibbs Free Energy, denoted by G, describes the energy available to do work within a system, in this case a chemical reaction.

Keep in mind that Free Energy, which is useful because it can be harnassed to do work, is different from the heat energy that is always lost in any process. This heat energy is generated as the cost of doing work, and is therefore often called nature&#039;s &quot;heat tax.&quot; The Gibbs Free Energy Change, or ΔG, is the difference between the G of the reactants and the G of the products.
ΔG = (energy of products) - (energy of reactants)

ΔG is useful because it tells us if a chemical reaction is likely to proceed in the direction it is written.
It doesn&#039;t indicate the Rate and is independent from Path of Reaction

Kinetically favourable reaction

Rreactions with a low ΔG‡

The reactants actually have to move through a higher energy state before they can arrive at the low energy state of the products. In other words, the reactants have to scale an "energy wall," called the Energy of Activation ( ΔG‡). The higher the ΔG‡, the taller the wall. As you might suspect, a taller wall is more difficult to scale, and thus reactions with a high ΔG‡ proceed slowly. In contrast, reactions with a low ΔG‡ progress more quickly. Such reactions are said to be kinetically favorable, or likely to proceed rapidly. (For more on biochemical kinetics, see the kinetics review.)

Thermodynamically favourable reaction

If the ΔG is negative, meaning the products are at a lower energy than the reactants,

Blood collected 20 years ago from a crime scene is being used for DNA testing at a murder trial to prove the suspect was indeed at the scene of the crime. The defense lawyer argues that this test cannot be reliable, since she knows that the hydrolysis reaction (breakdown) of DNA has a negative ΔG. She concludes that therefore the DNA degraded spontaneously after all this time, and is now useless. As an expert witness for the prosecution, how can you use your knowledge of biochemistry to explain why she is mistaken?

You point out that a negative ΔG just means the breakdown of DNA is thermodynamically favorable. You clarify this by explaining that the ΔG value does not say anything about how fast the reaction will occur. In fact, DNA is kinetically stable, and thus the breakdown of DNA happens very slowly, making DNA evidence valid decades after crimes have been commited.

Enthalpy (ΔH) vs Free Geebs Energy (ΔG)
Is any Exergonic reaction Exothermic?

Keep in mind that energy released in an exergonic reaction is not necessarily released as heat. Thus, an exergonic (energy releasing) reaction is not necessarily exothermic (heat releasing). In other words, a reaction with a negative ΔG (free energy) value may have either a positive or negative ΔH (enthalpy) value!

What are two components of Entropy?

Positional disorder and Thermal disorder.

Entalpy (H)

The Heat of the reaction

Enthalpy is denoted by the symbol H, and is a measure of the Internal Energy of a system. In the course of a reaction, the change in internal energy between reactants and products, or ΔH, can be measured by the heat absorbed or released during the course of a reaction (One caveat: this holds true as long as the reaction is performed under constant pressure, which is generally the case in biological systems). Because the enthalpy can be measured as heat, ΔH is often called the heat of reaction.

Reactions that consume enthalpy (have a positive ΔH) are said to be Endothermic (heat consuming), while reactions that release enthalpy (have a negative ΔH) are said to be exothermic (heat releasing).

Relationship between Free energy (Gibbs), Enthalpy and Entropy

ΔG = ΔH - TΔS
The T in the formula stands for the temperature at which the reaction occurs and is measured in degrees Kelvin, which are on the same scale as degrees Celsius, but start at absolute zero: K = °C + 273

The ΔH (enthalpy) term represents energy that can be measured as the evolution or absorption of heat during the course of the reaction.
The TΔS (entropy) term indicates energy associated with the change of entropy, or disorder, of the system during the course of the reaction.

Maximum usable potential energy of a reaction (ΔG) = Heat energy (ΔH) - Energy gained or lost due to changes in thermal and positional disorder of molecules (ΔS)

Any energy that is involved in increasing entropy (TxΔS) cannot be made to do useful work

Calculate the ΔG for the freezing of water at 0°C

The ΔG is zero because at 0°C, the liquid water and the solid ice are in equilibrium.

Unit of ΔG

J/mol

Unit of ΔH

J/mol

Unit of ΔS

J/(mol×K)

Polypeptide chains fold spontaneously into defined patterns to make functional proteins. This process involves the polypeptide chain going from a disordered, random structure to a highly ordered one. How is this not a violation of the Second Law of Thermodynamics?

When assessing entropic contributions to Gibbs Free Energy for the purpose of determining spontaneity, you must not look only at the system, but also at the surroundings. It is true that the entropy of the protein decreases when it is folded because the chain is arranged in a more orderly fashion. However, there are other entropic considerations in the surroundings of the protein. In an unfolded protein, all of the hydrophobic portions of the polypeptide are exposed to the aqueous environment, and the water molecules order themselves around the hydrophobic residues in ordered structures called hydration spheres. As a protein is folded, these hydrophobic residues initially exposed to the aqueous environment are buried in the interior of the protein, hidden away from contact with water molecules, and the entropy of the water molecules increases as the need for hydration spheres diminishes, in effect overcoming the entropy decrease for the protein alone. In other words, while the entropy of the system (the protein) decreases, the entropy of the surroundings increases to a greater degree, leading to an overall increase in entropy for the universe.

The folding of a protein also provides an example of the &quot;DH&quot; and &quot;-TDS&quot; terms competing with one another to determine the DG of the folding process. As described above, the change in entropy of the protein as it folds is negative, so the &quot;-TDS&quot; term is positive. However, in addition to entropic effects there are enthalpic contributions to protein folding. These include hydrogen bonding, ionic salt bridges, and Van der Waals forces. An input of thermal (heat) energy is required to disrupt these forces, and conversely when these interactions form during protein folding they release heat (the DH is negative). When all of these entropic and enthalpic contributions are weighed, the enthalpy term wins out over the entropy term. Therefore the free energy of protein folding is negative, and protein folding is a spontaneous process.

If in a reaction the ΔH is negative and ΔS is positive, then the reaction will be always Spontanous. True or False?

True.

In this case ΔH and -TΔS are both negative and the ΔG, which is the sum of them will be always negative regardless of their amount.

In other words:
It is a rection which wants to increase the entropy and decrease the enthalpy of the products and obviously it is spontanous.

ΔH: - and ΔS: + -----> ΔG: - always

If in a reaction the ΔH is positive and ΔS is negative what can be sayed about the spontaneity of the reaction.

Regardless of the amount of ΔH and ΔS this reaction is not spontanous. The sum of the ΔH and -TΔS are always positive.

It is a reaction which wants to decrease entropy (or makes the products more ordered) and also increase the enthalpy (the inner heat energy of the products)

ΔH: + and ΔS: - -----> ΔG: + always

If in a reaction ΔH and ΔS are both positive what can be sayed about the spontaneity of the reaction?

Nothing! in this case ΔH is positive and -TΔS is negative and these two terms compete with each other. The result is dependent of the amount of H, S and also T (Temperature of reaction)

It is a reaction which wants to increase the entropy (favourable) but at the same time increase the enthalpy of the products (unfavourable). It is not clear how much totally favourable it is.

ΔH: + and ΔS: + -----> ΔG: ? (+/- dependable)

If in a reaction ΔH and ΔS are both negative what can be sayed about the spontaneity of the reaction?

Nothing! in this case ΔH is negative and -TΔS is positive and these two terms compete with each other. The result is dependent of the amount of H, S and also T (Temperature of reaction)

It is a reaction which wants to decrease the entropy or make the products more ordered (unfavourable) but at the same time decrease the enthalpy of the products (favourable). It is not clear how much totally favourable this reaction is.

ΔH: - and ΔS: - -----> ΔG: ? (+/- dependable)

What happens to ΔG as ΔS gets smaller?

ΔG increases

For a nonspontanous reaction that demonstrate a positive change in both entropy and enthalpy, what can be easily done in lab to make it spontanous?

Increase temprature

For a nonspontanous reaction that demonstrate a negative change in both entropy and enthalpy, what can be easily done in lab to make it spontanous?

Decrease temprature

Kerb's cycle is not only important regarding Energy production, but also for providing substrates for Anabolic and biosynthetic processes. Name 4 important substrates and their metabolic fates.

Acetyl-CoA -----> Fatty acid
Citrate ----> Fatty acid
α-Ketoglutarate ----> Nonessential aminoacids
Succinyl CoA ----> Heme
Oxaloacetates ----> Glucose

In which step of Kerb's Cycle FAD is Reduced to FADH₂?

Succinate -----> Fumarate

In which step of Kerb's Cycle GTP is produced?

Succinyl CoA ----> Succinate

In which step of Kerb's Cycle NAD⁺ is Reduced to NADH?

1) Pyruvate ----> Acetyl-CoA

2) Isocitrate -----> α-Ketoglutarate
3) α-Ketoglutarate ----> Succinyl-CoA
4) Malate ----> Oxaloacetate

Note: (1) is the link reaction between Glycolysis and Kerb's Cycle

Controlled Enzymes Catalyzing irreversible Steps in Glycolysis?

1. Hexokinase and Glucokinase (Glucose ---> G6P)
2. PFK 1 (Fructose-6P ---> Fructose -1,6 bisP)
3. Pyruvate kinase (PEP ----> Pyruvate)

1. is the 1st step and 3. is the final step
2. is the Rate Limiting step

Hexokinase is controlled by

G6P, negative feedback

Glucokinase is controlled by

Glucokinase Regulatory Protein (GKRP) in Liver
Under control of Insuline

PFK is controlled by

F2,6BP and AMP ++
ATP, Citrate --

The above is true for PFK-1
for PFK-2 hormonal control is more important:
Insuline ++
Glucagon --

Insuline inhibits Glycogenolysis and stimulates Glycolysis. True or False?

True

What is the metabolic fate of the F-1,6-BP?

This C₆ molecules gives two C₃ molecules via Aldolase:
Glyceraldehyde-3P
Dihydroxyacetone-P (DHAP)

The first continues the glycolysis process, while the second is converted to Glycerol and is used in Triglycerid synthesis.

These two C₃ molecules can be converted to each other via Triose-Phosphate isomearse

Controlled Enzymes Catalyzing irreversible Steps in Citric Acid Cycle?

Citrate synthase (Acetyl-CoA ---> Citrate)
Isocitrate dehydrogenase (Isocitrate ---> α-Ketoglutarate)
α-Ketoglutarate dehydrogenase (α-Ketoglutarate ---> Succinyl CoA)

Citrate synthase is controlled by

ATP --

Isocitrate dehydrogenase is controlled by

ADP ++
ATP, NADH --

α-Ketoglutarate dehydrogenase is controlled by

ATP ,NADH, Succinyl CoA --

Clinical relevance of Complex IV of ETC?

Cytochrome c oxidase (Complex IV) is inhibited by: Cyanide
CO
Azide

β-Oxidation

Catabolism of fatty acids Yields:
Acetyl-CoA

Acetyl-CoA is utilized in TCA cycle.

in: Mitochondria

Carnitine Shuttle?

Carnitine transports long-chain acyl groups from fatty acids into the mitochondrial matrix, so that they can be broken down through β-oxidation to acetyl-CoA to obtain usable energy via the citric acid cycle

AcylcoA+Carnitine ---> Acylcarnitine + CoA
Acyl is transported to mitochondrion by Carnitine
In mitochondrion CoA binds to Acyl and relaese Carnitine:
Acylcarnitine + CoA ---> AcylcoA+Carnitine

Carnitine acetyltransferase 1

Acts in Cytosol:
Release CoA and Associate Carnitine with fatty acid:
Acetyl-CoA + Carnitine ----> Acetyl-carnitine + CoA

Carnitine acetyltransferase 2

Acts in Mitochondria:
Reassociates the fatty acid with CoA:
Acetyl-Carnitine + CoA ---> Acetyl-CoA + Carnitine

Which form of Glycogen Phosphorilase is Active: Phosphorylated or Dephosphorylated?

Phosphorylated
Glucagon phosphorylate (make it active)
Insuline dephosphorylate it (Make it inactive)

Epinephrin stimulates Glycogenolysis and inhibits Glycolisis in Liver. True or False?

True
It also stimulates Glycolysis in Muscle.

Allosteric inhibitors for Glycogen Phosphorylase?

ATP, Creatine phosphate, and G6P

Note: Creatine phosphate serves as a rapidly mobilizable reserve of high-energy phosphates in skeletal muscle and brain: Phosphocreatine can anaerobically donate a phosphate group to ADP to form ATP during the first 2 to 7 seconds following an intense muscular or neuronal effor

Regulation of Lipid Catabolism?

Lipase
Under control of:
Glucagon, Epinephrine and ACTH +++
Insuline ---

After degradation of Lipids to Free fatty acids by Lipase, there is no control:
Fatty acyl CoA Synthase is not controlled.

PPP Pathway?

Pentose Phosphate Passway

An alternative to Glycolysis for metabolism of Glucose
Anabolic:
Pentose: Ribose-5P ---> Nucleotid
NADPH ----> Important in biosynthesis of Fatty acid, Cholestrol and Steroids
Doesn't produce ATP

Glucose 6P + 2NADP⁺ + H₂O --> Ribose-5p + 2NADPH + 2H⁺ + CO₂

Ribose-5p ---> Glucose-6p via Ketolase

The Place for PPP Pathway (HMP Shunt)?

Cytosol

Not all cells:
Liver, Adipose tissue, Adrenal Cortex, Mammary glands, Testis, Erythrocytes

2 Phases of PPP Pathway?

1) Oxidative:
Produces NADPH,
Transketolase

2)Nonoxidative:
Produces the Pentose (Ribose-5P)
Transaldolase

Rate Limiting Step of PPP Pathway?

G6PD (Glucose-6P dehydrogenase):
Glucose-6P ---> 6-Phosphogluconolactone

Favism

The deficiency of G6PD
G6PD deficiency is the most common human enzyme defect
X-linked Recessive
Nonimmune Hemolytic Anemia in response to a number of causes, most commonly infection or exposure to certain medications or chemicals. (Hemolytic reaction to consumption of broad beans)

How G6PD deficiency causes hemolytic anemia?

NADPH is important for red blood cell metabolism.
NADPH Help RBCs to get rid of free radicals

In G6PD deficiency NADPH production via PPP Pathway decreases, Free radicals inside RBCs increases.

Effect of Insuline on:
Glucokinase

+++
Insuline stimulates Glycolysis

Effect of Insuline on:
PFK-2

+++
Insuline stimulates Glycolysis

Effect of Insuline on:
PFK-2

+++
Insuline stimulates Glycolysis

Effect of Insuline on Glycogen phosphorylase

---
Insuline is against Glycogenolysis

The enzyme is dephosphorilated by Insuline and become inactive

Effect of Insuline on Glycogen synthase

+++
Insuline is for Glycogen Synthesis

Effect of Glucagon and Epinephrin on Carbohidrate metabolism

+++ Glycogenolysis
+++ Gluconeogenesis

Rate limiting step in Fatty acid synthesis

Acetyl-CoA ---> Malonyl-CoA
in: Cytosol of Hepatocytes
Acetyl-CoA carboxylase (ACC)

Citrate-Malate Shuttle transports Acetyl groups
from Mitochondria ---> to Cytosol

Note: Glucagon and Epinephrine inhibits Acetyl-CoA carboxylase
Insuline, and Citrate stimulates it

Effect of Glucagon, Insuline and Epinephrine on Triglycerol Lipase

Glucagon and Epinephrin: ++ Stimulate lipase
Insuline; -- Inhibits lipase

Acetyl-CoA carboxylase (ACC)

Acetyl-CoA ---> Malonyl-CoA
A Biotin-dependent enzyme
Irreversible and Rate limiting Step in bio-synthesis of fatty acids

Cofactors of this enzyme are;
Vit H (Biotin) and Vit B₅ (Pantothenic acid)

Note: Glucagon and Epinephrine inhibits Acetyl-CoA carboxylase

Pantothenic acid?

Also called vitamin B5 (a B vitamin), is a water-soluble vitamin required to sustain life (essential nutrient). Pantothenic acid is needed to form coenzyme-A (CoA), and is critical in the metabolism and synthesis of carbohydrates, proteins, and fats.

Peroxisome?

Peroxisomes are organelles present in almost all eukaryotic cells. They participate in the metabolism of fatty acids and many other metabolites. Peroxisomes harbour enzymes that rid the cell of toxic peroxides.

The β-Oxidation of Unsaturated, Odd-chain, and Very-long-chain fatty acids requires additional enzymes, some of them in peroxisomes

One round of β-Oxidation yields:

1 FADH₂
1 NADH
1 Acetyl-CoA

Each Acetyl-CoA in TCA cycle Yields:
1 GTP
1 FADH
3 NADH

Total Sum:
1 GTP
2 FADH ----> 4 ATP
4 NADH -----> 12 ATP
----------
Equivalent to 17 ATP
Minus 2 ATP consumption for fattyacyl Activation
----------
Final result = 15 ATP

Each Acetyl-CoA molecule yields energy equivalent to --- ATP

12
Each Acetyl-CoA in TCA cycle Yields:

1 GTP---->1 ATP
1 FADH--->2 ATP
3 NADH--->9 ATP
-----------------
12 ATP

If a saturated fatty acids goes through 10 round of β-Oxidation to be completely oxidesed, How many ATPs is produced from this fatty acid?

[(10 × 17)-2] + 12 = 180

After 10 rounds of β-Oxidation a final product of one free Acetyl CoA is remained which can produce more 12 ATP in TCA cycle!

The energy yield of complete oxidation of a saturated fatty acid with 16 Carbon is equivalent to ---- ATP.

ATP = (n/2-1)x17-2+12=(n/2-1)x17+10
=7x17+10=129

Note: each round of β-Oxidation picks up 2 carbons from molecule in form of Acetyl-CoA (C₂)

Laurate is a saturated fattyacid with the formula:
CH₃(CH₂)₁₀COO⁻. The energy yield of complete oxidation of Laurate is equivalent to ---- ATP.

95
Laurate has 12 Carbon and goes trough 12/2-1=5 rounds of β-Oxidation
(12/2-1)x17+10

Each double bound in odd number position costs --- ATP and each double bound in even number position costs --- ATP

2, 3

The energy yield of complete oxidation of a fatty acid with 12 carbon and two double bonds at C₃-C₄ and C₆-C₇ is equivalent to --- ATP

(12/2-1)x17+10=95
Correction: 95-3-2=90

The energy yield of complete oxidation of a saturated fatty acid with 23 Carbon is equivalent to ---- ATP.

[ (n-1)/2-1 ] +10 + 8
Calculate it for a fatty acid with 22 carbon and then add 8 ATP

Essentially, to get rid of the one extra carbon atom (Propionyl-CoA), one ATP molecule was invested, and the process produced the equivalent of nine additional ATP. Therefore, to calculate the energy yield of the complete β-Oxidation of an odd-chain fatty acid, add eight to the total for a fatty acid with one less carbon atom.

What is different in β-Oxidation of Very long chain fatty acids?

Fatty acids with chains that contain 22 or more carbon atoms are called very-long-chain fatty acids.
Very-long-chain fatty acids begin β-Oxidation in the Peroxisomes.

This process is almost identical to β-Oxidation in the mitochondria, with one key difference. Instead of reducing ubiquinone in the first step, the peroxisomes produce hydrogen peroxide. This peroxide can be used in other reactions to oxidize toxic substances in the cell. Each round of β-Oxidation in the peroxisomes produces the equivalent of 15 molecules of ATP—two less than β-Oxidation in the mitochondria. However, peroxisomes usually do not completely degrade the fatty acids. Because the enzymes in peroxisomes have a low affinity for short-chain fatty acids, shortened fatty acids are transported to the mitochondria to finish β-Oxidation.

If a fatty acid with even number of carbons goes through 7 rounds of β-oxidation to be completely oxidized, howmany carbon atom does it have?

16

A saturated fatty acid with 24 carbon atoms undergoes 5 rounds of β-Oxidation in Peroxisome and then passes to a mitochoindrion where it udergoes complete β-Oxidation. What is the total energy yield of this fatty acid?

The 5 rounds of β-Oxidation in the peroxisome yield (5×15)=75 ATP, leaving a 24-(5×2)=14 carbon fatty acid. This fatty acid undergoes 6 more rounds of β-Oxidation in the mitochondria, for a total energy yield of :
75+(6×17)+12-2=187

Coenzyme A (CoA)

A coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle.

It assists in transferring fatty acids from the cytoplasm to mitochondria. (Since coenzyme A is chemically a thiol, it can react with carboxylic acids to form thioesters, thus functioning as an acyl group carrier.)

Triglycerides are hydrolized to Glycerol and Fatty acids, Which both can yield energy. True or False?

True:
Fatty acids undergo β-Oxidation
Glycerol-->Glycerol-3P-->Glucose-6p -->Glycolysis

What are the metabolic fates of Acetyl-CoA?

1) Producing Energy in TCA in cycle
2) Fatty acid synthesis
3) Cholestrol and Ketone bodies synthesis (via HMG-CoA)

HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme A

In certain metabolic states such as --- and --- much of the Acetyl-CoA is converted to Ketone-bodies.

Diabetes Mellitus
Starvation

Keton bosies?
Which one is used for energy production?

Acetone
Acetoacetate
β-Hydroxybutarate

Acetone is not used for enegy production.

Amino acids are used to synthesize ---

1) Other Amino acids
2) Metabolic Intermediates: Pyruvate, Acetyl-CoA, , Oxaloacetate, Succinyl-CoA, and α_Ketoglutarate

Proteins, Lipids and Carbohydrates can be converted to Acetyl-CoA.
True/False?

True

In humans, Fatty acids can not be converted to Glucose.
True/False?

True

Coenzyme for Transamination?

Vit B₆ (Pyrodoxine)

Transamination of Piruvate to Alanine

Yields: Alanine + α-Ketoglutarate or Oxaloacetate

Transamination of Alanine to Piruvate

Yields: Piruvate + Glutamate or Aspartate

Medically relevant Transaminase enzymes

1) in MI: AST (Aspatate aminotransferase)
2) in Liver Cirrhosis: ALT (Alanine aminotransferase)

Entner-Duodoroff Pathway

Glycolytic pathway in Aerobic Bacteria

Glucose --> Pyruvate + Glyceraldehyde-3p
1 ATP (Substarte level phosphorylation)

Fatty acid synthase (FAS)

Fatty acid synthase (FAS) is a multi-enzyme it plays a key role in fatty acid synthesis. It is not a single enzyme but a whole enzymatic system composed of multifunctional polypeptide, in which substrates are handed from one functional domain to the next.

Responsible for synthesis of Palmitic acid (one of the most abundant and important fatty acids)

Packaging several enzyme activities into one multifunctional protein like mammalian fatty acid synthase allows the synthesis to be faster and controlled in a coordinated fashion. Also, the product of one reaction can quickly diffuse to the next active site.

Glycerol phosphate serves as the initial acceptor of the fatty acid in TG synthesis. The source of Glycerol phosphate?

1) From: Glycolysis
2) Synthesized in Liver from Glycerol

Rate Limiting Step in Cholestrol synthesis?

HMG-CoA Reductase:
HMG-CoA ---> Mevalonate

FAD and NAD derivatives of which vitamins?

FAD from Riboflavin = Vit B₂
NAD from Niacin = Vit B₃

Enzyme responsible for converting Galactose to Glucose?

Galactose-1-phosphate uridylyltransferase (or GALT) UDP-glucose + galactose 1-phosphate ----> glucose 1-phosphate + UDP-galactose

Deficiency of Galactose-1-phosphate uridylyltransferase (or GALT) results in Severe Galactosemia

UDP-Glucose?

Uridine diphosphate glucose (UDP-glucose) is a precursor of glycogen and can be converted into UDP-galactose and UDP-glucuronic acid, which can then be used to make polysaccharides containing galactose and glucuronic acid.

UDP-glucose can also be used as a precursor of sucrose lipopolysaccharides, and glycosphingolipids.

Phosphoglucose isomerase?

Glucose-6-phosphate isomerase, (alternatively known as phosphoglucose isomerase or phosphohexose isomerase), is an enzyme that catalyzes the conversion of glucose-6-phosphate into fructose 6-phosphate in the second step of glycolysis.

Transketolase

In the pentose phosphate pathway (PPP)
Thiamine diphosphate-mediated transfer of a 2-carbon fragment from D-xylulose-5-P to the aldose erythrose-4-phosphate, affording fructose 6-phosphate and glyceraldehyde-3-P.

In mammals, Transketolase connects the pentose phosphate pathway to glycolysis, feeding excess sugar phosphates into the main carbohydrate metabolic pathways.

Deficiency in enzyem: ---- causes Severe Galactosemia

Galactose-1p Uridyl transferase:
Galactose-1p + UDP-Glucose ---> Glucose-1p + UDP-Galactose

Galactose-1-phosphate uridylyltransferase (or GALT) is an enzyme responsible for converting ingested galactose to glucose.

UDP-glucose pyrophosphorylase?

Glucose-1-phosphate uridylyltransferase (or UDP-glucose pyrophosphorylase) is an enzyme associated with glycogenesis. It synthesizes UDP-glucose from glucose-1-phosphate and UTP

Glucose-1-phosphate + UTP &lt;---&gt; UDP-glucose + pyrophosphate

Glycogene Synthase?

Glycogen synthase (UDP-glucose-glycogen glucosyltransferase') is an enzyme involved in converting glucose to glycogen. It takes short polymers of glucose and converts them into long polymers.

It is a glycosyltransferase enzyme that catalyses the reaction of UDP-glucose and (1,4-α-D-glucosyl)n to yield UDP and (1,4-α-D-glucosyl)n+1.

Maturity onset diabetes of the young (MODY)

Refers to any of several hereditary forms of diabetes caused by mutations in an autosomal dominant gene disrupting insulin production.
MODY is often referred to as "monogenic diabetes" to distinguish it from the more common types of diabetes (especially type 1 and type 2), which involve more complex combinations of causes involving multiple genes (i.e., "polygenic") and environmental factors.

Note: Mutations in Enzyme Glucokinase may also lead to form MODY

GLUT

Glucose Transporter

Because glucose is a polar molecule, transport through biological membranes requires specific transport proteins.

1) Secondary Active Transport:
Secondary active Na+/glucose symporters, SGLT-1 and SGLT-2
Intestine, Kidney

2) Facilitated Diffusion:
GLUT

GLUT 1

Basal uptake (All tissues)

GLUT 2

Liver: Storage
β-Islets: Glucose Sensor

GLUT 4

Important for Insulin: Muscle, Addipose tissue

Physical Excercise --> Growth of Muscles ---> Increase in GLUT 4

Phosphoenolpyruvate carboxykinase (PEPCK)?

Phosphoenolpyruvate carboxykinase (PEPCK) is an enzyme used in the metabolic pathway of gluconeogenesis. It converts oxaloacetate into phosphoenolpyruvate and carbon dioxide.

Oxaloacetate (C₄)----> PEP (C₃) + CO₂

Metabolism of Fruktose

1) Fruktose ---> Fructose-1P
2) Fructose-1P (C₆) ---> DHAP + Glyceraldehyde
3) DHAP ---> Glyceraldehyde-3P
4) Glyceraldehyde ----> Glyceraldehyde-3P

Enzymes: 1) Fructokinase, 2) Aldolase B, 3) Triose-phosphate isomerase, 4) Glyceraldehyde kinase

Glyceraldehyde-3P continues the Glycolisis process.

Glyceraldehyde 3-phosphate dehydrogenase (GAPDH)

6th step of glycolysis
Glyceraldehyde 3-phosphate ---> D-glycerate 1,3-bisphosphate

One NADH produced at this step

Essential Fructosuria

Dficiency in Fructokinase
Also known as Hepatic Fructokinase Deficiency or Ketohexokinase Deficiency
Leading to fructose being excreted in the urine.
A benign condition, as fructose cannot be broken down, so it is simply excreted in the urine.
Autosomal recessive.

Fructosemia (Fructose Intolerance)

Dficiency in Aldolase B
Fructose in the blood
A very serious condition, as fructose is converted into and building up fructose-1-phosphate in the blood. This prevents proper release of glucose from glycogen, uses up free phosphate, and causes a rise in uric acid, leading to growth abnormalities and, in severe cases, coma.

Galctosemia

Mild: deficiency in Galactokinase
Severe: dficiency in Galactose-1p uridyltransferase

Ketogenesis

Mitochondrial Matrix of Liver cells.
In response to low glucose levels in the blood, and after exhaustion of cellular carbohydrate stores, such as glycogen (e.g. Fasting, Diabetes Melitus)

The production of ketone bodies is then initiated to make available energy that is stored as fatty acids. Fatty acids are enzymatically broken down in β-oxidation to form acetyl-CoA.
Under normal conditions, acetyl-CoA is further oxidized in the citric acid cycle (TCA cycle).
However, if the amounts of acetyl-CoA generated in fatty-acid β-oxidation challenge the processing capacity of the TCA cycle or if activity in the TCA cycle is low due to low amounts of intermediates such as oxaloacetate, acetyl-CoA is then used instead in biosynthesis of ketone bodies via acetoacetyl-CoA and β-hydroxy-β-methylglutaryl-CoA (HMG-CoA).

Besides its role in the synthesis of ketone bodies, HMG-CoA is also an intermediate in the synthesis of cholesterol.

Malonyl-CoA

Plays a key role in Fatty acid biosynthesis.

Acetyl-CoA ---> Malonyl-CoA , via:
acetyl-coA carboxylase (Biotin + Pantothenic acid)

Malonyl-CoA is also used in transporting alpha-ketoglutarate across the mitochondrial membrane into the mitochondrial matrix.

Rate Limiting Step in Fatty acid synthesis

Acetyl-CoA Carboxylase
Acetyl CoA + HCO₃⁻ + ATP ---> Malonyl-CoA + ADP + H⁺

Biotin (Vit H) and Pantothenic acid (Vit B₅)

+: Citrate, Insulin
-: Glucagon, Epinephrin

Role of Citrate in Fatty acid synthesis

Citrate from CTA cycle can be transported out of the mitochondria and into the cytoplasm, then broken down into acetyl CoA for fatty acid synthesis.

Citrate is a positive modulator of this conversion and allosterically regulates the enzyme acetyl-CoA carboxylase, which is the regulating enzyme in the conversion of Acetyl CoA into malonyl CoA (the commitment step in fatty acid synthesis).

In short: Citrate is transported to the cytoplasm, converted to Acetyl CoA which is converted into Malonyl CoA by the Acetyl CoA carboxylase enzyme which is allosterically modulated by citrate.

Substrates for Gluconeogenesis

1. Pyruvate
2. All citric acid cycle intermediates, through conversion to oxaloacetate
3. Amino acids other than lysine or leucine
4. Glycerol

Fatty acids cannot be converted into glucose in animals with the exception of odd-chain fatty acids, which yield propionyl CoA, a precursor for succinyl CoA

Activator of Plasminogen?

Urokinase from kidney
Plasminogen--> Plasmin --> Lysis of Fibrin

Autodigestion of Pancreas

In Acute Pancreatitis:

The exocrine pancreas produces a variety of enzymes, such as proteases, lipases, and saccharidases. These enzymes contribute to food digestion by breaking down food tissues.

In Acute Pancreatitis, the worst offender among these enzymes may well be the protease trypsinogen which converts to the active trypsin.
Trypsin is most responsible for auto-digestion of the pancreas which in turn causes the pain and complications of pancreatitis.

Remember: Trypsin can activate all other Zymogens of pancreas (Can convert even Trypsinogen and all other zymogens to their active form)

Glycogenolysis in muscle can not increase the Blood Sugar Level.
True or False?

True

Glucose-6-Phosphatase doe not exist in Muscle. it is specific for Liver.

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