Part 3 espyr1 S6c

1

Cellular Metabolism III

Lipid Metabolism

- Carbon chains in highly reduced form

o Oxidation of lipids releases large quantities of energy than carbohydrates - Fatty acids in triacylglycerols are principal storage form of energy for most organisms - Triacylglycerol can be hydrolysed by a hormone known as lipase to free fatty acids

- Our bodies should not synthesize fatty acids from phosphatidylcholine as it is our cell membrane, if fatty acids are synthesized this way, we are in trouble!!!

- Hormone bind to the receptor of the plasma membrane of the adipocyte

Activation of Fatty Acid

- Fatty acids  acyl CoA

o Form thioester bond between COO^- group and the thiol group of CoA-SH o Large free energy is produced - Step 1: Reaction of AMP to free fatty acid

o ATPAMP+PPⁱAMP+2Pⁱ o Activation of Fatty Acid: -2 ATP o Occurs in cytosol

- Step 2: Reaction of the RCO-AMP with CoASH - Final Product: Acyl CoA

o This catalytic reaction occurs on outer mitochondrial membrane catalysed by acyl-CoA synthase

Transport to Mitochondria

- Acyl-CoA transferred to the intermembrane space

- Acyl Group transferred to carnitine o Carnitine+AcylAcyl-Carnitine o CoASH go back to the outer

membrane to be reused o Catalysed by Carnitine

acyltransferase I - Acyl-Carnitine transferred to the

matrix

o React with mitochondrial CoASH

o Acyl-Carnitine + CoASH Acyl CoA β-oxidation

o Catalysed by Carnitine acyltransferase II

Activated Fatty Acid

2

β-Oxidation

- In mitochondrial matrix

- Cleaves 2 C at a time from carboxyl end of a fatty acids

- 4 steps: Oxidation  Hydration + FADH²

 Oxidation +NADHCleavage

Odd Numbered Fatty Acids

- The oxidation will stop until it is 3 Carbons left

- The compound is known as propionyl CoA

- It will enter enzymatic pathways to give a Final Product of Succinyl CoA by consuming 1 ATP

- Enters the citric acid cycle

ATP Yield

=_{−2 +}ⁿ

2 3 × 2.5 + 1.5 + 1 + ⁿ₂− 1 2.5 + 1.5

=ⁿ 2 ^{10 +}

n 2^{− 1 4}

= ₋

ATP yield for saturated even numbered Fatty acids - Number of carbon =n (even number) and n_{≥ 2} - Activation of Fatty acid = -2 ATP

- ⁿ

2 Acetyl CoA

- ⁿ

2− 1 β-oxidation cycle

ATP Yield =_{−2 +}^{n− 3}

2 3 × 2.5 + 1.5 + 1 +^{n− 3}

2 2.5 + 1.5 + 1 2.5 + 1.5 + 1 − 1

=−2 + 7 n − 3 + 4

= _{− �}

Saturated Odd-numbered fatty acids - Number of C= n (odd) and n_{≥ 3} - Activation of Fatty Acid=-2 ATP

- ⁿ⁻³

2 Acetyl CoA

- ⁿ⁻³

2 β-oxidation

- Convert Propinoyl CoA Succinyl CoA= -1 ATP

- One Succinyl CoA = At the middle of citric acid cycle = 1 NADH + 1 ATP + 1 FADH2

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Monounsaturated Fatty Acids

- The fatty acid will oxidize until at the point where the double bond is situated two carbons away from the acyl group

- Then the enzyme ∆^3,∆²− enol − CoA − isomerase catalyses the isomerisation from cis to trans (MUST TRANS!!!!)

- β-oxidation continues

Polyunsaturated Fatty Acids

- Another enzyme is needed to transfer the two double bonds to ONE double bond

- 2,4- Dienoyl-CoA reductase - 1 NADPH is used (-2.5 ATP)

- BEWARE: Only fatty acids with configuration of this kind of

double bond is applicable (i.e. 18: 2(_∆⁹,_∆¹²)), that is the double bonds are separated by one C-C carbon ONLY

Ketone Bodies

- When bodies has insufficient energy, body will use up proteins, after that, fats will be broken down - When fats are broken down, there is a lot of Acetyl CoA

- They will be converted to ketone bodies o _Acetone

o β-Hydroxybutyrate o Acetoacetate

- Principally in liver mitochondria

- Can be used as fuel in most tissues and organs

ATP Yield = 7n− 19 − 1.5

= ₋ .

ATP Yield = 7n_{− 6 − 1.5}

= _{− .}

Monounsaturated fatty acids - Number of C=n - -1 FADH₂ - If n is odd,

- If n is even,

ATP Yield = ₋ . _{− .} ATP Yield = _{− . − .} Polyunsaturated Fatty Acid - Number of C= n

- Number of extra double bond = m

- -2.5 ATP from the monounsaturated equation - If n is odd,

- If n is even,

4 - Occurs when

o Intake high in lipids and low in carbohydrates o Diabetes not suitably controlled

o Undergoing starvation - Begins with TWO acetyl CoA

- Ketone bodies are potentially danger substances in our bodies if it is accumulated long-term in our bodies

- 2 Acetyl CoAAcetoacetyl CoAHMG-CoAAcetoacetateAcetone OR D-β-hydroxybutyrate

Synthesis of Amino Acids

Glutamate Family

- Glutamate is major donor of amino groups in reactions - α-ketoglutarate is major acceptor amino groups - Glutamate  Glutamine

o Inorganic nitrogen fixation reactions o Forming organic nitrogen compounds

- The process requires energy : 1 NADPH and 1 ATP = 3.5 ATP

Reductive amination (glutamate dehydrogenase)

Amidation (Glutamine synthetase)

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Pyridoxal Phosphate

- A cofactor for the synthesis of amino acids - Active form of vitamin B6

- Participates in the catalysis of amino acid reactions o Transamination, decarboxylations, etc - Transamination reaction

o Formation of Imine (Schiff Base) o Rearrangement of isomeric imine

o Hydrolysis of isomeric imine to form α-ketoacid and pyridoxamine

Serine Family

- 3 phosphoglycerate act as a precursor for synthesis of serine o Oxidation of precursor to α-keto acid

o Transamination reaction with glutamate (requires PyrP) o Hydrolysis of phosphate group

Serine _{ Glycine}

- Conversion of Serine to Glycine is a one carbon transfer reaction - Requires a cofactor : Tetrahydrofolate (THF), derived from folic acid

o Accept β-carbon (C3) in serine

o Reduction of folic acid  Tetrahydrofolic acid o Requires 2 NADPH = -5 ATP

- Catalysed by serine hydroxymethyl transferase

Enzyme

One carbon transfer

PyrP

PyrP (Coenzyme)

6 Serine Cysteine

- Different mechanisms in animals and plants - In plants and bacteria

o Acetylation of Serine to O-acetyleserine (by serine acyltransferase) o O-acetylserine  Cysteine (requires Sulphide S^2-)

o Derived from environmental sulphates

- Sulphate is activated via formation of PAPS (3’-Phosphoadenosine 5’- phosphosulphate)

- PAPS undergoes 8 electron reduction

- _PAPSSO3^2- (sulphite) (2 e-)_S^2- (sulphide) (6 e-)

- In animals, methionine (essential amino acids) is required o Involves S-adenosylmethione (SAM)

o Then demethylated to form S-adenosylhomocysteine (SAH) by methylating a methyl acceptor - SAH is hydrolysed to produce homocysteine

- Homocysteine + Serine  cystathionineα- ketobutyrate + cysteine

- In animals, there are two amino acids o Methionine to provide sulphur atom o Serine to provide carbon backbone

From Ser

From met