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compound with
in vitro
efficacy and specificity for the potassium channels [see references
in: 33].
To summarise, although the yeast genome has been completed for more than eight
years, the majority of yeast gene functions are still poorly characterised. However, many of
the approaches presented in Miami have the potential to assign functions to significant
portions of the yeast proteome. As knowledge of yeast cell biology expands, one can expect
greater light to be reflected on all eukaryotes and further use of yeast for pharmacological
applications.
3.2 Genome sequencing of Streptomyces species
Streptomycetes belong to Gram-positive, mycelial, spore-forming soil bacteria with two
important properties. They have an unusual genomic topology of very large linear replicons
and synthesise a large number of secondary metabolites, many of which have important
pharmacological properties. It is, therefore, not surprising that they have a significant
biodiversity potential.
Genetic biodiversity potential of
Streptomyces
species can be illustrated by the
following facts. Streptomycetes have linear chromosomes from 8 to 9 Mb, about twice the
size of
Escherichia coli
(4.6 Mb [28]) or
Bacillus subtilis
(4.2 Mb [27]) chromosomes
containing 4,288 and 4,100 protein-coding genes, respectively. The chromosome of
S.
coelicolor
, a model
Streptomyces
species sequenced recently at Sanger Centre [29], is
8,667,507 bp long containing 7,846 protein-coding genes. If one assumes that the known
common functions of all saprophytic bacteria for catabolism, metabolism, DNA replication,
protein synthesis etc., require at most 4 Mb of coding DNA, the remaining 4 Mb of
Streptomyces
DNA might be species specific. The other question is, what is the structural
biodiversity potential of their secondary metabolism? It is well known that out of 19,000
antibiotically active compounds isolated from bacteria to mammals, Streptomycetes
synthesise 7,900. Moreover, 75% of all antibiotics important in human and veterinary
medicine are produced by
Streptomyces
species [34]. Watve and his collaborators [35] have
recently attempted to estimate the number of the yet undiscovered antimicrobials from this
genus. The model they developed has shown that the total number of antimicrobial
compounds this genus is capable of producing is in the order of 100,000 - less than 10% of
what has been discovered so far.
Each
Streptomyces
species is capable of synthesising more than one biologically
active secondary metabolite. For example, it has been known that
S. coelicolor
synthesises
at least four antibiotics: actinorhodin, undecylprodigiosin, methylenomycin and lipopeptide
antibiotic CDA. However, the analysis of
S. coelicolor
genome sequence, and the genome
sequence of avermectin producing
S. avermitilis
, suggests that there are many (more than
20) gene-clusters coding for secondary metabolites in each species, which have not yet
been analysed [29, 30].
Streptomyces
secondary metabolites can interact with a number of
biological targets such as yet unidentified proteins of different organelles (like ribosomes,
membranes, microtubules, chloride ion channels etc.) nucleic acids (both DNA and RNA)
and individual proteins (like RNA polymerase, HMG-CoA reductase, FK protein, etc.). It
is, therefore, not surprising that
Streptomyces
antibiotics, antifungals, citostatics,
immunosuppressants, anticholesterolemics, antiparasitics, coccidiostatics, animal growth
promotants and natural insecticides are in commercial use [34]. The main point now is how
to use this enormous biodiversity potential?
Streptomyces
secondary metabolites withstand simple chemical classification, but
many best-understood and biologically most active compounds are synthesised by two
families of multifunctional enzymes that can assemble unusual carbon and peptide chains,
which have important medical, veterinary and agrochemical properties. Polyketide and
