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BC21D: Bioenergetics & Metabolism
The formation of Acetyl Coenzyme A; Krebs cycle;
electron transport chains and chemiosmotic
phosphorylation mechanism:
FADNAD+
FADH2
NADH
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.
BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A
PyruvateDehydrogenaseComplex
PyruvateCarboxylase
Metabolic relationship betweencarbohydrate and fat catabolism
Some amino acids
BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A
1. Glycolysis by either the EMP pathway, or variants such as PPP/HMP.
BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A
Recall that PK is an important regulatory enzyme in some cells.
BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A
2. Aerobic oxidation of lactate, e.g. by heart or liver isoenzymes of Lactate dh.
BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A
3. Oxidative deamination of alanine, e.g. by liver after release from skeletal muscle during fasting.
BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A
Lets us now look at pyruvate dehydrogenase
BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A
BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A
BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A
BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A
pdh reaction mechanism
E1 = Pyruvate dehydrogenaseE2 = Dihydrolipoyl transacetylaseE3 = Dihydrolipoyl dehydrogenase
BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A
Pdh is regulated by reversible, inhibitory phosphorylation of E1.
BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A
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
BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A
Apart from carbohydrates, carbons from other molecules can form acetyl CoA.
CHO
BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A
Parts of leucineisoleucinetryptophan
are degraded to acetyl CoA
BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A
Lets us now look at fatty acid degradation
BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A
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.
BC21D: Bioenergetics & Metabolism The formation of Acetyl Coenzyme A
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
BC21D: Bioenergetics & Metabolism
BC21D: Bioenergetics & Metabolism
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
BC21D: Bioenergetics & Metabolism
Aconitase
Aconitase
Aconitate is not normally released from the enzyme
Aconitase contains an iron-sulphur centre
BC21D: Bioenergetics & Metabolism
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.
NAD+
BC21D: Bioenergetics & Metabolism
α-ketoglutarate dehydrogenase complex
NADH + H+
NAD+
Another control point of the Krebs cycle
BC21D: Bioenergetics & Metabolism
(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.
BC21D: Bioenergetics & Metabolism
Succinate thiokinase
GTP
GDP + Pi
BC21D: Bioenergetics & Metabolism
Succinate dehydrogenase complex
FADH2
BC21D: Bioenergetics & Metabolism
Malate dehydrogenase
NADH + H+
BC21D: Bioenergetics & Metabolism
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.
BC21D: Bioenergetics & Metabolism
Possible metabolic outputs from the Krebs cycle
From Nelson & Cox
BC21D: Bioenergetics & Metabolism
From Stryer
BC21D: Bioenergetics & Metabolism
Anaerobes lacking α-KG dh therefore have an incomplete Krebs cycle.
BC21D: Bioenergetics & Metabolism
Some plants, invertebrates and fungi have the glyoxylate cycle for converting two acetates into succinate, thus are able to use fatty acids for gluconeogenesis.
BC21D: Bioenergetics & Metabolism
electron transport & bioenergetics BC21D: Bioenergetics & Metabolism
electron transport & bioenergetics BC21D: Bioenergetics & Metabolism
electron transport & bioenergetics BC21D: Bioenergetics & Metabolism
Collecting light energy from the solar (or an artificial) source is a major alternative to carbon catabolism.
electron transport & bioenergetics BC21D: Bioenergetics & Metabolism
Recall this image from last year. It highlights the similarities between different energy metabolisms.
electron transport & bioenergetics BC21D: Bioenergetics & Metabolism
electron transport & bioenergetics BC21D: Bioenergetics & Metabolism
electron transport & bioenergetics BC21D: Bioenergetics & Metabolism
electron transport & bioenergetics BC21D: Bioenergetics & Metabolism
electron transport & bioenergetics BC21D: Bioenergetics & Metabolism
electron transport & bioenergetics BC21D: Bioenergetics & Metabolism
electron transport & bioenergetics BC21D: Bioenergetics & Metabolism
electron transport & bioenergetics BC21D: Bioenergetics & Metabolism
electron transport & bioenergetics BC21D: Bioenergetics & Metabolism
electron transport & bioenergetics BC21D: Bioenergetics & Metabolism
electron transport & bioenergetics BC21D: Bioenergetics & Metabolism
electron transport & bioenergetics BC21D: Bioenergetics & Metabolism
electron transport & bioenergetics BC21D: Bioenergetics & Metabolism
Diagram from Lodish et al
electron transport & bioenergetics BC21D: Bioenergetics & Metabolism
electron transport & bioenergetics BC21D: Bioenergetics & Metabolism
electron transport & bioenergetics BC21D: Bioenergetics & Metabolism
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chemiosmotic mechanism BC21D: Bioenergetics & Metabolism
The generation of a proton motive force across a biomembrane is a common bioenergetic mechanism.
79
chemiosmotic mechanism BC21D: Bioenergetics & Metabolism
Proton gradients
are used to drive a
number of energy
consuming reactions.
80
chemiosmotic mechanism BC21D: Bioenergetics & Metabolism
81
chemiosmotic mechanism BC21D: Bioenergetics & Metabolism
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chemiosmotic mechanism BC21D: Bioenergetics & Metabolism
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