Page 145 - Color Atlas of Biochemistry

136 Metabolism

+
Tricarboxylic acid cycle: reactions p. 134). NADH+H is once again formed in
this reaction.
The tricarboxylic acid cycle (TCA cycle, also [5] The subsequent cleavage of the thio-
known as the citric acid cycle or Krebs cycle) ester succinylCoA into succinate and coen-
is a cyclic metabolic pathway in the mitochon- zyme A by succinic acid-CoA ligase (succinyl
drial matrix (see p. 210). In eightsteps, itoxi- CoA synthetase, succinic thiokinase) is
dizesacetyl residues(CH 3 -CO-) to carbon di- strongly exergonic and is used to synthesize
oxide (CO 2 ). The reducing equivalents ob- a phosphoric acid anhydride bond (“substrate
tained in this process are transferred to level phosphorylation ”, see p.124). However, it
+
NAD or ubiquinone, and from there to the is not ATPthat isproduced here as isother-
respiratory chain (see p. 140). Additional met- wise usually the case, but instead guanosine
abolic functions of the cycle are discussed on triphosphate (GTP). However, GTP can be con-
p. 138. verted into ATP by a nucleoside diphosphate
kinase (not shown).
[6] Via the reactions described so far, the
A. Tricarboxylic acid cycle
acetyl residue has been completely oxidized
The acetyl-CoA that supplies the cycle with to CO 2 . At the same time, however, the carrier
acetyl residues is mainly derived from E- molecule oxaloacetate has been reduced to
oxidation of fatty acids (see p. 164) and from succinate. Three further reactions in the cycle
the pyruvate dehydrogenase reaction. Both of now regenerate oxaloacetate from succinate.
these processes take place in the mitochon- Initially, succinate dehydrogenase oxidizes
drial matrix. succinate to fumarate. In contrast to the other
[1] In the first step of the cycle, citrate enzymesinthecycle,succinatedehydrogenase
synthase catalyzes the transfer of an acetyl isanintegralproteinoftheinnermitochondrial
residue from acetyl CoA to a carrier molecule, membrane. It is therefore also assigned to the
oxaloacetic acid. The product of this reaction, respiratory chain as complex II. Although suc-
tricarboxylic acid, gives the cycle its name. cinate dehydrogenase contains FAD as a pros-
[2] In the next step, tricarboxylic acid thetic group, ubiquinone is the real electron
undergoes isomerization to yield isocitrate. acceptor of the reaction.
In the process, only the hydroxyl group is [7] Water is now added to the double bond
shifted within the molecule. The correspond- of fumarate by fumarate hydratase (“fuma-
ing enzyme is called aconitate hydratase rase”), and chiral (2S)-malate is produced.
(“aconitase”), because unsaturated aconitate [8] In the last step of the cycle, malate is
arises as an enzyme-bound intermediate dur- again oxidized by malate dehydrogenase into
+
ing the reaction (not shown; see p. 8). Due to oxaloacetate,with NADH+H again being pro-
the properties of aconitase, the isomerization duced. With this reaction, the cycle is com-
is absolutely stereospecific. Although citrate is plete and can start again from the beginning.
not chiral, isocitrate has two chiral centers, so As the equilibrium of the reaction lies well on
that it could potentially appear in four iso- thesideofmalate, theformation of oxaloace-
meric forms. However, in the tricarboxylic tic acid by reaction [8] depends on the
acid cycle, only one of these stereoisomers, strongly exergonic reaction [1], which imme-
(2R,3S)-isocitrate, is produced. diately removes it from the equilibrium.
[3] The first oxidative step now follows. The net outcome is that each rotation of
Isocitrate dehydrogenase oxidizes the hy- the tricarboxylic acid cycle converts one ace-
droxyl group of isocitrate into an oxo group. tyl residue and two molecules of H 2 Ointotwo
At thesametime, a carboxylgroup is released molecules of CO 2 . At the same time, one GTP,
+
as CO 2 ,and 2-oxoglutarate (also known as α- three NADH+H andone reducedubiquinone
+
ketoglutarate) and NADH+H are formed. (QH 2 ) are produced. By oxidative phosphory-
[4] The next step, the formation of succinyl lation (see p. 122), the cell obtains around
CoA, also involves one oxidation and one de- nine molecules of ATP from these reduced
carboxylation. It is catalyzed by 2-oxogluta- coenzymes (see p. 146). Together with the
rate dehydrogenase, a multienzyme complex directly formed GTP, this yields a total of 10
closely resembling the PDH complex (see ATP per acetyl group.

Koolman, Color Atlas of Biochemistry, 2nd edition © 2005 Thieme
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