BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A; Krebs cycle; electron...

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BC21D: Bioenergetics & Metabolism

The formation of Acetyl Coenzyme A; Krebs cycle;

electron transport chains and chemiosmotic

phosphorylation mechanism:

andrew.pearson@uwimona.edu.jm

FADNAD+

Pyruvate and acetyl CoA are important metabolites at the intersection of many carbon-

metabolising pathways.

BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A

Pyruvate and acetyl CoA are important metabolites at the intersection of many carbon-

metabolising pathways.

PyruvateDehydrogenaseComplex

PyruvateCarboxylase

Metabolic relationship betweencarbohydrate and fat catabolism

Some amino acids

1. Glycolysis by either the EMP pathway, or variants such as PPP/HMP.

Recall that PK is an important regulatory enzyme in some cells.

2. Aerobic oxidation of lactate, e.g. by heart or liver isoenzymes of Lactate dh.

3. Oxidative deamination of alanine, e.g. by liver after release from skeletal muscle during fasting.

Lets us now look at pyruvate dehydrogenase

pdh reaction mechanism

E1 = Pyruvate dehydrogenaseE2 = Dihydrolipoyl transacetylaseE3 = Dihydrolipoyl dehydrogenase

Pdh is regulated by reversible, inhibitory phosphorylation of E1.

Pdh is regulated by 4 reversible, inhibitory kinases of E1. The kinases have differing tissue specificities.

The kinases are activatedby increasing the ratiosof: [NADH]/[NAD];

[acetyl CoA]/[CoA]; [ATP]/[ADP]

The kinases are inhibited by pyruvate.

Insulin stimulates dephosphorylyation.

Pyruvate dehydrogenase kinases 1 – 4, with different tissue specificities

“Pyruvate dehydrogenase kinase”, actually….

Phosphorylation sites onPdh subunit E1

Pyruvate dehydrogenase complex

Pyruvate dehydrogenase phosphatase

Regulation of the Pyruvate Dehydrogenase Complex

Apart from carbohydrates, carbons from other molecules can form acetyl CoA.

Parts of leucineisoleucinetryptophan

are degraded to acetyl CoA

Lets us now look at fatty acid degradation

BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme AFigure 3 Modulation of CPT I activity by carbohydratesThe pathway shown in red is the established pathway for the inhibition of hepatic CPT activity by carbohydrates. The other pathways shown are alternative routes that may be operative in heart Abbreviations : CPT, carnitine palmitoyl transferase ; CAT, carnitine acetyl transferase.

Just to remind you wherewe are going with this!

The major metabolic role of the Krebs cycle in most aerobes is the oxidative degradation of acetate to two molecules of CO2 and some high energy reducing equivalents.

The Krebs cycle

Citrate synthase

This is control point in some bacteria: the Krebs cycle is not partitioned from the cytosol.

ATP is a negative modulator, raising the enzyme’s Km value for acetyl CoA

Aconitase

Aconitate is not normally released from the enzyme

Aconitase contains an iron-sulphur centre

Isocitrate dehydrogenase

NADH + H+

This is one of the control points of the Krebs cycle.It is an allosteric enzyme: ADP is the positive modulator enhancing the binding of isocitrate and NAD+.

NADH is a competitive inhibitor of NAD+ binding.

ATP also inhibits.

α-ketoglutarate dehydrogenase complex

NADH + H+

Another control point of the Krebs cycle

(a) animal α-KG dh is very sensitive to ADP, Pi, and Ca2+;

(b) these positive effectors increase the affinity of α-KG dh to α -ketoglutarate;

(c) α-KG dh is inhibited by ATP, NADH, and succinyl-CoA;

(d) the ATP effect is realized mainly via opposition to ADP activation;

(e) NADH, in addition to inhibiting the dihydrolipoamide dehydrogenase component of the enzyme complex (competitively versus NAD+), decreases the affinity of

α -ketoglutarate dehydrogenase to its substrate;(f) bacterial and plant α-KG dh are activated by AMP instead of

ADP. These main effects form the basis of short term regulation of α-KG dh.

Succinate thiokinase

GDP + Pi

Succinate dehydrogenase complex

Malate dehydrogenase

NADH + H+

Amino acids can feed their carbons into the Krebs cycle for gluconeogenesis.

Recall when and in which cells this occurs.

BC21D: Bioenergetics & MetabolismAmino acids with direct linkages to the Krebs cycle

are especially important.

Possible metabolic outputs from the Krebs cycle

From Nelson & Cox

From Stryer

Anaerobes lacking α-KG dh therefore have an incomplete Krebs cycle.

Some plants, invertebrates and fungi have the glyoxylate cycle for converting two acetates into succinate, thus are able to use fatty acids for gluconeogenesis.

electron transport & bioenergetics BC21D: Bioenergetics & Metabolism

Collecting light energy from the solar (or an artificial) source is a major alternative to carbon catabolism.

Recall this image from last year. It highlights the similarities between different energy metabolisms.

Diagram from Lodish et al

chemiosmotic mechanism BC21D: Bioenergetics & Metabolism

The generation of a proton motive force across a biomembrane is a common bioenergetic mechanism.

Proton gradients

are used to drive a

number of energy

consuming reactions.

BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A; Krebs cycle; electron...

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