Introduction to Enzyme and Coenzyme Chemistry - E-Library Home

166 Chapter 7
CoAS
O
EnzB −
H
D
T
k H /k T = 2.7
H
O
−
O CO 2
CoAS
D T
inversion of configuration
CoAS
O OH
−
CO 2
D T
H 2 O
− O 2 C
−
CO 2
D
76% loss of 3 H
fumarase
(anti-elimination)
OH
− O 2 C
− CO 2
D T
major product
corresponding
to removal of H
Figure 7.12 Stereochemistry of the malate synthase reaction.
however, the enzymatic reaction is made eVectively irreversible by the subsequent
hydrolysis of malyl CoA to malic acid. It is not known exactly how the
formation of the thioester enolate (or enol) is made possible at the enzyme
active site, but there must be signiWcant stabilisation of this intermediate in situ
by the enzyme.
7.4 Assembly of fatty acids and polyketides
Acetyl CoA is also used in the formation of the carbon chains of fatty acids and
polyketide natural products in biological systems. Fatty acids are long-chain
carboxylic acids, such as stearic acid (C 17 H 35 CO 2 H), which are found widely as
triglyceride esters in the lipid component of living cells. Polyketide natural
products are assembled from a polyketide precursor containing ketone functional
groups on alternate carbon atoms. In many cases these polyketide
precursors are cyclised to form aromatic compounds, such as orsellinic acid
shown in Figure 7.13.
There are many similarities between fatty acid biosynthesis and polyketide
biosynthesis: they are both assembled from acyl CoA thioesters via a series of
Claisen-type reactions by multi-enzyme synthase complexes (fatty acid synthase
or polyketide synthase). The assembly is carried out via stepwise addition of
two-carbon units onto a growing acyl chain which is attached to an acyl carrier
protein (ACP) via a thioester linkage.
The Wrst acetyl unit is transferred from acetyl CoA onto the acyl carrier
protein, but thereafter the substrate for carbon–carbon bond formation is
malonyl CoA, formed by carboxylation of acetyl CoA (described in Section
7.5). The malonyl group is transferred from malonyl CoA onto the acyl carrier
protein by an acyltransferase (AT) activity (see Figure 7.14). Carbon–carbon
bond formation is achieved by attack of the a-carbon of the malonyl-thioester