Transcript BC21D: Bioenergetics & Metabolism

BC21D: Bioenergetics & Metabolism
The formation of Acetyl
Coenzyme A; Krebs cycle;
electron transport chains and
chemiosmotic
phosphorylation mechanism:
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FAD
NAD+
FADH2
NADH
BC21D: Bioenergetics & Metabolism
The formation of Acetyl Coenzyme A
Pyruvate and acetyl CoA are
important metabolites at the
intersection of many carbonmetabolising pathways.
BC21D: Bioenergetics & Metabolism
The formation of Acetyl Coenzyme A
Pyruvate and acetyl CoA are
important metabolites at the
intersection of many carbonmetabolising pathways.
Metabolic relationship between
carbohydrate and fat catabolism
Pyruvate
Carboxylase
Pyruvate
Dehydrogenase
Complex
Some amino acids
The formation of Acetyl Coenzyme A
BC21D: Bioenergetics & Metabolism
1.
Glycolysis by either the
EMP pathway, or variants
such as PPP/HMP.
BC21D: Bioenergetics & Metabolism
Recall that PK is an
important regulatory
enzyme in some
cells.
The formation of Acetyl Coenzyme A
The formation of Acetyl Coenzyme A
BC21D: Bioenergetics & Metabolism
2.
Aerobic oxidation of
lactate, e.g. by heart or liver
isoenzymes of Lactate dh.
The formation of Acetyl Coenzyme A
BC21D: Bioenergetics & Metabolism
3.
Oxidative deamination
of alanine, e.g. by liver after
release from skeletal
muscle during fasting.
BC21D: Bioenergetics & Metabolism
Lets us now
look at pyruvate
dehydrogenase
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
BC21D: Bioenergetics & Metabolism
pdh reaction
mechanism
E1 = Pyruvate dehydrogenase
E2 = Dihydrolipoyl transacetylase
E3 = Dihydrolipoyl dehydrogenase
The formation of Acetyl Coenzyme A
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 activated
by increasing the ratios
of:
[NADH]/[NAD];
[acetyl CoA]/[CoA];
[ATP]/[ADP]
The kinases are inhibited by pyruvate.
Insulin stimulates dephosphorylyation.
Regulation of the Pyruvate Dehydrogenase
Complex
Pyruvate dehydrogenase
phosphatase
“Pyruvate dehydrogenase
kinase”, actually….
Pyruvate dehydrogenase
complex
Phosphorylation sites on
Pdh subunit E1
Pyruvate dehydrogenase
kinases 1 – 4, with different
tissue specificities
The formation of Acetyl Coenzyme A
BC21D: Bioenergetics & Metabolism
Apart from
carbohydrates,
carbons from
other
molecules can
form acetyl
CoA.
CHO
BC21D: Bioenergetics & Metabolism
Parts of
leucine
isoleucine
tryptophan
are degraded
to acetyl CoA
The formation of Acetyl Coenzyme A
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
The formation of Acetyl Coenzyme A
BC21D: 3Bioenergetics
& Metabolism
Figure
Modulation
of CPT I activity by carbohydrates
The 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 where
we 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.
BC21D: Bioenergetics & Metabolism
The Krebs cycle
BC21D: Bioenergetics & Metabolism
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
Citrate synthase
BC21D: Bioenergetics & Metabolism
Aconitase
Aconitase
contains an
iron-sulphur
centre
Aconitate is not
normally released
from the enzyme
Aconitase
BC21D: Bioenergetics & Metabolism
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.
Isocitrate
dehydrogenase
NAD+
NADH + H+
BC21D: Bioenergetics & Metabolism
Another control point
of the Krebs cycle
NAD+
α-ketoglutarate
dehydrogenase
complex
NADH + H+
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
FADH2
Succinate
dehydrogenase
complex
BC21D: Bioenergetics & Metabolism
NADH + H+
Malate
dehydrogenase
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
& Metabolism
Amino
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
BC21D: Bioenergetics & Metabolism
electron transport & bioenergetics
BC21D: Bioenergetics & Metabolism
electron transport & bioenergetics
BC21D: Bioenergetics & Metabolism
electron transport & bioenergetics
Collecting light energy from the solar (or an
artificial) source is a major alternative to carbon
catabolism.
BC21D: Bioenergetics & Metabolism
electron transport & bioenergetics
Recall this image from
last year. It highlights
the similarities
between different
energy metabolisms.
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
electron transport & bioenergetics
Diagram from Lodish et al
BC21D: Bioenergetics & Metabolism
electron transport & bioenergetics
BC21D: Bioenergetics & Metabolism
electron transport & bioenergetics
BC21D: Bioenergetics & Metabolism
electron transport & bioenergetics
BC21D: Bioenergetics & Metabolism
chemiosmotic mechanism
The generation of a
proton motive force
across a
biomembrane is a
common
bioenergetic
mechanism.
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BC21D: Bioenergetics & Metabolism
chemiosmotic mechanism
Proton
gradients
are used to
drive a
number of
energy
consuming
reactions.
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chemiosmotic mechanism
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chemiosmotic mechanism
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