Chemistry Reference
In-Depth Information
Biotin (
6
, Fig. 10.10) and lipoic acid (
7
, Fig. 10.1) are attached enzymatically
to apoenzymes via carboxamide linkage to specific lysine residues (60, 61). The
pantothenyl moiety (
64
, Fig. 10.7) can also be linked covalently to proteins via
amide linkage (62). Covalently bound heme is involved in heme M (63) and
heme L-catalyzed reactions (64, 65).
Several covalently bound coenzymes, including pyruvoyl, methylidine imida-
zolone, topaquinone, and tryptophan tryptophyl quinine-type prosthetic groups
are generated by posttranslational modification (66).
10.2.17 Cellular Topology of Coenzyme Biosynthesis in Eukaryotes
In bacteria, coenzyme biosynthesis is located in the cytoplasm. In eukaryotic
cells, organelles play important roles in the biosynthesis of certain cofactors. For
example, certain steps of iron/sulfur cluster biosynthesis proceed in mitochondria
(10, 13). In plants, some steps of the biosynthesis of tetrahydrofolate, biotin, and
lipoate proceed in mitochondria (7, 15), whereas the biosynthesis of vitamin B
2
is
operative in plastids (67). In apicomplexan protozoa, enzymes in mitochondria,
the apicoplast (an organelle that is believed to have a common evolutionary
origin with chloroplasts), and the cytoplasmic compartment must cooperate for
the biosynthesis of tetrapyrrole cofactors, thiamine, and isoprenoid cofactors (68,
69). The biosynthesis of carotenoids proceeds via the nonmevalonate pathway
in the chloroplasts of plants (52). The same holds true for the biosynthesis of
thiamine, pyridoxal, and chlorophyll (70).
10.2.18 Three-Dimensional Structures of Coenzyme Biosynthesis Enzymes
The rapid technological progress in X-ray crystallography has enabled the struc-
tural analysis of numerous enzymes involved in coenzyme biosynthesis. Complete
sets of structures that cover all enzymes of a given pathway are available in cer-
tain cases such as riboflavin, tetrahydrobiopterin, and folic acid biosynthesis.
Structures of orthologs from different taxonomic groups have been reported in
certain cases. X-ray structures of enzymes in complex with substrates, prod-
ucts, and analogs of substrates, products, or intermediates have been essential
for the elucidation of the reaction mechanisms. Structures of some coenzyme
biosynthesis enzymes have been obtained by NMR-structure analysis.
Enzymes that are addressed by major drugs have been studied in particular
detail. Thus, well above one hundred structures have been reported for dihydro-
folate reductases from a variety of organisms, including major pathogens such
as
Mycobacterium tuberculosis
, which is the causative agent of tuberculosis, and
of
Plasmodium falciparum
, which is the most important of the
Plasmodium
spp.
that causes malaria. The interaction of mammalian dihydrofolate reductases with
inhibitors that are used as cytostatic agents and/or immunosuppressants is also
documented extensively by X-ray structures.
The rapidly growing number of three-dimensional coenzyme biosynthesis
enzyme
structures
in
the
public
domain
and
the
cognate
publications
are
best
addressed
via
the
internet
server
of
Brookhaven
Protein
Data
Bank
