Download Ch t 19 apter 19 The Citric Acid Cycle

Mary K. Campbell
Shawn O. Farrell
http://academic.cengage.com/chemistry/campbell
Chapter
Ch
t 19
The Citric Acid Cycle
Paul D. Adams • University of Arkansas
Major pathways of glucose utilization
1
4
2
3
C6H12O6+6O2+6H2O Æ 6CO2+12H2O+energy
Mary K. Campbell
Shawn O. Farrell
http://academic.cengage.com/chemistry/campbell
Chapter
Ch
t 19
The Citric Acid Cycle
Paul D. Adams • University of Arkansas
The Central Role of the Citric Acid Cycle
• Cellular aerobic metabolism
• The citric acid cycle (CA cycle)
• Electron transport (Chapter 20)
• Oxidative phosphorylation (Chapter 20)
• Metabolism consists of
• Catabolism(
Catabolism(分解代謝）
分解代謝）:: the oxidative breakdown of
nutrients
• Anabolism
Anabolism（合成）
（合成）:: the reductive synthesis of
biomolecules
amphibolic（兩義）：
（兩義）：catabolism
• The citric acid cycle is amphibolic
and anabolism.
p
y
• It is the central metabolic pathway
The Central Relationship of the Citric Acid
y
to Catabolism
Cycle
cytosol
Mitochondria
matrix
Mitochondria
inner membrane
Where does the Citric Acid Cycle Take
Place?
• In eukaryotes, cycle takes place in the mitochondrial matrix
Features of Cycle
Pyruvate transporter
Mitochondria matrix
Irreversible
Features of Cycle
Pyruvate is Converted to Acetyl-CoA
• Pyruvate dehydrogenase (PDH) complex is
responsible for the conversion of pyruvate to CO2
and the acetyl portion of acetyl-CoA
• Five enzymes in PDH complex: pyruvate
dehydrogenase, dihydrolipoyl transacetylase,
dihydrolipoyl dehydrogenase, pyruvate
dehydrogenase kinase, pyruvate dehydrogenase
phosphatase
• Why?
The Mechanism of the Pyruvate
y g
((PDH)) Complex
p
Dehydrogenase
Reduced lipoylysine
Co-factor: Thiamin pyrophosphate (TPP), lipoic acid, Flavin adenine
dinucleotide (FAD)
Rate-limiting
step
Summary
• The two-carbon unit needed at the start of the citric
acid cycle is obtained by converting pyruvate to
acetyl-CoA
• This
Thi conversion
i requires
i
th
the th
three primary
i
enzymes
of the pyruvate dehydogenase complex, as well as,
th cofactors
the
f t
TPP
TPP, FAD,
FAD NAD+,
NAD+ and
d lipoic
li i acid
id
• The overall reaction of the pyruvate dehydogenase
complex is the conversion of pyruvate, NAD+, and
CoA-SH to acetyl-CoA, NADH + H+, and CO2
Diseases related to the PDH complex (TPP):
1 Thiamine deficiency: unable to oxidize pyruvate
1.
pyruvate,
alcholism
2. Beriberi（腳氣病）, thiamine deficiency disease:
loss of neural function
Individual Reactions of the Citric Acid Cycle
• In step 1, there is a condensation of acetyl-CoA with
oxaloacetate to form citrate
• ΔG°’ = -32.8 kJ•mol-1, therefore, the reaction is exergonic
step 1
• Reaction is catalyzed by citrate synthase, an allosteric
enzyme that is inhibited by NADH, ATP, and succinyl-CoA
Individual Reactions of the Citric Acid Cycle
(
(Cont’d)
)
isomerization
step 2
Individual Reactions of the Citric Acid Cycle
(
(Cont’d)
)
• In step 3, there is an
step 3
oxidation of isocitrate
followed by decarboxylation
to form α-ketoglutarate and
CO2
isocitrate
• The reaction is catalyzed by
isocitrate dehydrogenase,
an allosteric enzyme, which
is inhibited by ATP and
NADH and activated by
NADH,
ADP and NAD+
ATP
NADH
ADP
NAD+
decarboxylation
Individual Reactions of the Citric Acid Cycle
(
(Cont’d)
)
• In step 4, there is an oxidative decarboxylation of αketoglutarate to succinyl-CoA
step 4
α-ketoglutarate dehydrogenase
complex
• This reaction is catalyzed by the α-ketoglutarate
α ketoglutarate
dehydrogenase complex, which is, like pyruvate
dehydrogenase, a multienzyme complex and requires
coenzyme A, thiamine pyrophosphate, lipoic acid, FAD, and
NAD+
Individual Reactions of the Citric Acid Cycle
(
(Cont’d)
)
• Next, the thioester bond of succinyl-CoA if hydrolyzed in the
formation of succinate
• The two CH2-COO- groups of succinate are equivalent
gy y
g step
p ((GTP)) of the cycle
y
• This is the first energy-yielding
• The overall reaction is slightly exergonic
step 5
Individual Reactions of the Citric Acid Cycle
(
(Cont’d)
)
• Next, there is an oxidation of succinate to fumarate
step
p6
• Then, the hydration of fumarate to L-malate occurs
step 7
Individual Reactions of the Citric Acid Cycle
(
(Cont’d)
)
• Then, malate is oxidized to Oxaloacetate
step 8
Oxidation of Pyruvate Forms CO2 and ATP
Summary
• In the citric acid cycle and the pyruvate
dehydrogenase reaction
reaction, one molecule of pyruvate is
oxidized to three molecules of CO2 as a result of
oxidative decarboxylation
• The oxidations are accompanied by reductions
involving NAD+ to NADH, FAD to FADH2
• GDP is phosphorylated to GTP (substrate
phosphorylation)
Control of the Citric Acid Cycle
• There are 3 points of control within the cycle:
• Citrate synthase
synthase:: inhibited by ATP
ATP, NADH,
NADH and
succinyl CoA; also product inhibition by citrate
• Isocitrate
I
it t dehydrogenase
d h d
dehydrogenase:
: activated
ti t d by
b ADP and
d
NAD+, inhibited by ATP and NADH
• α-ketoglutarate
k t l t
t dehydrogenase
d h d
complex
complex:
l : inhibited
i hibit d
by ATP, NADH, and succinyl CoA; activated by ADP
and NAD+
• There is one control point outside the cycle
• Pyruvate dehydrogenase:
dehydrogenase: inhibited by ATP and
NADH; also product inhibition by acetyl-CoA
Control of the Citric Acid Cycle (Cont’d)
Energetics of the Citric Acid Cycle
ATP
Control of the Citric Acid Cycle (Cont’d)
The Citric Acid Cycle in Catabolism
• The catabolism of proteins, carbohydrates, and fatty acids all
feed into the citric
acid cycle at one or more points
Protein
Protein
Summary
• All metabolic pathways are related, and all of them
operate simultaneously
• In catabolic pathways, nutrients, many of which are
macromolecules, are broken down to smaller
molecules, such as sugars, fatty acids, and amino
acids
• Small molecules are processed further, and the end
products of catabolism frequently enter the citric acid
cycle, which plays a key role in metabolism
The Citric Acid Cycle in Anabolism
• The citric acid cycle is the source of starting
materials for the biosynthesis of other compounds
• If a component of the citric acid cycle is taken out for
biosynthesis, it must be replaced
• oxaloacetate, for example, is replaced by the
carboxylation of pyruvate
• A reaction that replenishes a citric acid cycle
intermediate is called an anaplerotic reaction
（補給反應）
The Citric Acid Cycle in Anabolism (Cont’d)
The Citric Acid Cycle in Anabolism (Cont’d)
Lipid Anabolism
• Lipid anabolism begins with acetyl-CoA and takes
place in the cytosol
• acetyl-CoA is produced mainly in mitochondria from
catabolism of fatty acids and carbohydrates
• an indirect transfer mechanism exists involving citrate
Citrate + CoA-SH + ATP -----> Acetyl-CoA + Oxaloacetate + ADP + Pi
• the oxaloacetate thus formed provides a means for
th production
the
d ti off the
th NADPH needed
d d ffor bi
biosynthesis
th i
Lipid Anabolism (Cont’d)
Oxaloacetate + NADH + H+ ----> Malate + NAD+
Malate + NADP+ ----> Pyruvate + CO2 + NADPH + H+
• The
Th the
th nett effect
ff t off these
th
two
t
reactions
ti
is
i
replacement of NADH by NADPH
• While
Whil th
there iis some NADPH produced
d
db
by thi
this means,
its principal source is the pentose phosphate
pathway
• The anabolic reactions that produce amino acids and
many other biomolecules begin with CA cycle
molecules that are transported into the cytosol
Summary of Anabolism in the Citric Acid
y
Cycle
Summary
• The citric acid cycle plays a central role in anabolic
pathways as well as in catabolism
• P
Pathways
h
that
h give
i rise
i to sugars, ffatty acids,
id and
d
amino acids all originate with components of the
citric
it i acid
id cycle
l
The Link To Oxygen
• The citric acid cycle is considered part of the aerobic
metabolic process because of its link to the electron
transport chain and oxidative phosphorylation
• NADH and FADH2, two important cofactors
generated by the citric acid cycle, ultimately pass
their electrons to oxygen