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Encyclopedia of Physical Science and Technology EN017G-116 August 2, 2001 18:14

524 Vitamins and Coenzymes

carriers of the single-carbon compounds CO 2 , bicarbon-
ate ions, formaldehyde, and formic acid. The combining of
biotin with CO 2 is not a spontaneous process but depends
upon adenosine triphosphate (ATP), which serves as both
a phospho group carrier and the common energy currency
for many cellular reactions. It can also be regarded as a
coenzyme. In order to be activated by reaction with ATP,
the CO 2 must first combine with a hydroxide ion to form
−
bicarbonate HCO . ATP then transfers a phospho group
3
to the bicarbonate, forming the labile and short-lived car-
−
boxyl phosphate ( OOC O PO ) together with adeno-
2−
3
sine diphosphate (ADP). The carboxyl phosphate, in turn,
transfers the carboxyl group to the biotin prosthetic groups
of the various carboxylase proteins. From them the car-
boxyl group is transferred onto the various sites marked by
arrows in Fig. 17. An inorganic phosphate ion is released
when the carboxyl group is transferred to biotin, complet-
FIGURE 17 The carboxyl carrier function of biotin. A molecule of ing a sequence that couples activation of CO 2 with the

activated CO 2 is carried as COOH bonded to N−1 of biotin, cleavage of ATP to ADP and inorganic phosphate (P i ).
which is covalently attached (as in Fig. 11) to an appropriate Such coupling of ATP cleavage to biosynthesis is a com-
protein. Below this structure the sites of four different metabolic
mon feature of much of biosynthetic metabolism.
intermediates that receive activated CO 2 from carboxybiotin are
marked by arrows. In each case, either the thioester linkage to Two other biotin-dependent reactions of great signif-
coenzyme A or another adjacent carbonyl group activates a hydro- icance are the carboxylation of acetyl-CoA to malonyl-
gen atom which dissociates as H , leaving a negatively charged CoA and that of pyruvate to oxaloacetate (Fig. 17). The
+
site which accepts the CO 2 by direct transfer from carboxybi- former is essential to biosynthesis of fatty acids, which
otin. Carboxylation of propionyl-CoA in the human body is an are formed in a pathway which parallels (in reverse) that
essential step in degradation of branched chain and odd chain-
length fatty acids (Fig. 12). The resulting methylmalonyl-CoA is of β oxidation (Fig. 12). However, there are several dif-
converted to succinyl-CoA, the reverse of the reaction shown in ferences. In the biosynthetic pathway, acetyl-CoA is first
Fig. 16. converted to malonyl-CoA which undergoes decarboxyla-
tion when a two-carbon unit is added to the growing fatty
acid chain. This decarboxylation, together with the prior
group X is often attached via a C C bond which is broken. carboxylation steps, couples ATP cleavage to the biosyn-
The net result is that a hydrogen atom trades places with thesis. Furthermore, NADPH is used in the reduction steps
group X. These rearrangement reactions, which cannot rather than NADH or FADH 2 . In addition, the acyl carrier
be catalyzed by proteins alone or by other coenzymes, is not coenzyme A but the related prosthetic group of acyl
are quite numerous in various bacteria. However, only carrier protein. Another biosynthetic process that depends
one of them occurs in human cells. That is the conver- upon biotin is the synthesis of glucose in the liver. Pyru-
sion of methylmalonyl-CoA to succinyl-CoA, the reverse vate, a product of glucose breakdown, is carboxylated to
of the succinyl-CoA mutase reaction as drawn in the oxaloacetate which is later decarboxylated on its pathway
lower section of Fig. 16. The reaction is essential to the to glucose. Again ATP cleavage is coupled to biosynthesis
metabolism of propionyl-CoA as is indicated at the bot- with the help of biotin.
tom of Fig. 12. Propionyl-CoA is carboxylated at the site Tetrahydrofolates (THF) interconvert several one-
marked by an arrow in Fig. 17 to form methylmalonyl- carboncompoundsorfragments.AsisindicatedinFig.18,
CoA. This compound must be isomerized by the vitamin formaldehyde released from the PLP-dependent cleavage
B 12 -dependent mutase to form succinyl-CoA which can be of serine is immediately trapped by THF (Fig. 14). Nitro-
oxidized to CO 2 in the body’s central metabolic pathways. gen N1 adds to formaldehyde to form a carboxymethyl
Lack of the mutase is fatal. ( CH 2 COOH) derivative which can than react re-
versibly with loss of water to form a cyclic adduct
10
(Fig. 18). This compound can be oxidized to the N -
D. Carriers of Single-Carbon Compounds,
methyl form. Both of these are important intermediates
and Other Roles of Pterin Coenzymes
in a variety of biosynthetic processes. The third one-
The three coenzymes biotin, tetrahydrofolate, and the carbon carrier is vitamin B 12 which can act as an accep-
vitamin B 12 derivative methylcobalamin (Fig. 7) act as tor, taking the methyl group from methyl-THF to form