2.

Overproduction of Metabolites

Due to some aberration in their regulatory mechanisms, organisms are often found in nature
which overproduce metabolites. When these compounds have medical, nutritional, or industrial
importance, the producing organisms are subjected to intensive development. Over a period of years,
production of some fermentation products has been increased over 1000-fold by a combination of
genetic and environmental manipulations. Environmental manipulations often involve the testing of
hundreds of additives as possible precursors of the desired product. Occasionally, a precursor is found
which increases production and/or directs the formation of one specific desirable product among a
family of structurally similar products. Examples of such cases of "directed biosynthesis" include
phenylacetic acid in the benzylpenicillin fermentation, amino acids in the production of actinomycins
and tyrocidines, substituted benzoic acids in the formation of novobiocins and 5,6-
dimethylbenzimidazole in the production of vitamin B~2. In many fermentations, however, precursors
produce no benefits because their syntheses are not rate-limiting. In such cases, screening of additives
has revealed dramatic effects, both stimulatory and inhibitory, of nonprecursor molecules. These effects
are due to interaction of nonprecursor compounds with the residual regulatory mechanisms present in
the fermentation organism

2. Produksi Metabolit Berlebih

Karena beberapa penyimpangan dalam mekanisme pengaturannya, organisme sering ditemukan di alam
yang memproduksi metabolit secara berlebihan. Ketika senyawa ini memiliki kepentingan medis, nutrisi,
atau industri, organisme penghasil mengalami pengembangan yang intensif. Selama beberapa tahun,
produksi beberapa produk fermentasi telah meningkat lebih dari 1000 kali lipat dengan kombinasi
manipulasi genetik dan lingkungan. Manipulasi lingkungan sering kali melibatkan pengujian ratusan
aditif sebagai kemungkinan prekursor dari produk yang diinginkan. Kadang-kadang, prekursor
ditemukan yang meningkatkan produksi dan / atau mengarahkan pembentukan satu produk tertentu
yang diinginkan di antara satu keluarga produk yang secara struktural serupa. Contoh kasus seperti
"biosintesis terarah" termasuk asam fenilasetat dalam fermentasi benzilpenisilin, asam amino dalam
produksi aktinomisin dan tirosidin, asam benzoat tersubstitusi dalam pembentukan novobiocins dan 5,6-
dimetilbenzimidazol dalam produksi vitamin B ~ 2. Namun, dalam banyak fermentasi, prekursor tidak
menghasilkan manfaat karena sintesisnya tidak membatasi laju. Dalam kasus seperti itu, skrining aditif
telah mengungkapkan efek dramatis, baik stimulasi maupun penghambatan, dari molekul nonprecursor.
Efek ini disebabkan oleh interaksi senyawa non-prekursor dengan mekanisme pengaturan residu yang
ada dalam organisme fermentasi

a) Primary Metabolites
Primary metabolites are the vital small molecules of all living cells which are used as building
blocks for essential macromolecules or are converted into coenzymes. The most important,
from the industrial point of view, are the amino acids, nucleotides, and vitamins. The feedback
type of regulation has proved to be most important in the fermentative biosynthesis of such
products. In order to bypass feedback regulation, two types of manipulation have been
employed: (1) decrease in the concentration of an inhibitory or repressive end product; (2)
mutational alteration of the enzyme or enzyme-forming system to a condition less sensitive to
feedback effects, i.e. mutation to feedback resistance.
 Decrease in Concentration of End Products. In a simple pathway this principle is used to
accumulate intermediates. For example, in Fig. 3, if one desires to accumulate compound C, an
auxotrophic mutant is first