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Endogenous
yeast enzymes do not have the ability to make hydrocortisone.
However, certain mammalian enzymes do have this ability. Thus,
by studying mammalian hydrocortisone biosynthesis, a strategy
to genetically engineer yeast to make this seroid can be devised.
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Yeast Cannot Synthesize
Hydrocortisone
- Although, yeast can't make hydrocortisone,
it does synthesize ergosterol, a steroid that can
be converted into hydrocortisone through a series a intermeadiates
produced by mammalian enzymes.
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Figure 3A: Yeast make ergosterol,
but
cannot convert it to hydrocortisone.
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- In order for yeast to make hydrocortisone,
they must possess, in a functional form, enzymes capable of
carrying out hydrocortisone synthesis using ergosterol as a
substrate.
- However, the normal mammalian biosynthetic
pathway for hydrocortisone uses cholesterol (LINK) substrate.
Thus, yeast must also have enzymes capable of converting ergosterol
into a substrate that is closely analogous to cholesterol.
- Mammalian enzyme activities can be introduced
to yeast through transfection with the mammalian genes
for the respective enzymes.
- Among other problems to solve in this
endeavor, yeast normally have some
other enzymes that hinder hydrocortisone production. Thus,
it is also necessary to "program" the yeast
to stop making these enzymes.
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Mammalian
Hydrocortisone Synthesis
- Several mammals (including humans)
do synthesize this hydrocortisone.
- In humans, hydrocortisone is synthesized
in the adrenal cortex.
- Hydrocortisone is a glucocorticoid,
and regulates gluconeogesis and other metabolic pathways.
- Glucocorticoids are also potent anti-inflammitory
agents, are are used for many theraputic
purposes.
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Figure 3B: In humans, hydrocortisone is synthesized in
the adrednal cortex.
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Mammalian
Biosynthetic Pathway
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- In mammals, a complex biosynthetic
pathway which involves several enzymes converts cholesterol
into hydrocortisone.
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| Figure 3C: In mammals, several enzymes
are used to synthesize hydrocortisone. |
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