Unexpected connection between nickel toxicity, cholesterol found

Context: Every so often, researchers discover a connection
between what were believed to be completely unrelated phenomena. A team from
the University of Georgia in the U.S. published one such report in the journal PLoS
Genetics on September 16. They discovered that exposing mammalian and
fungal cells to the heavy metal nickel resulted in sterol deficiency. Additionally,
tolerance to nickel was found to increase when the fungal cells overexpressed a
gene called ERG25, which encodes an enzyme. Cells unable to increase levels of
the ERG25 enzyme were unable to grow in the presence of a higher nickel
concentration. Until this report, no one suspected nickel toxicity was related
to sterol biosynthesis in fungi and animals.

Key points

·      
Use of Nickel: Nickel was once used commonly to secure earrings in
pierced ears, but it soon became clear that in a significant fraction of people
it was a contact allergen. Nickel compounds are also known to be carcinogenic. In
the wild, on the other hand, plants, bacteria, and fungi need nickel for the
normal function of an important enzyme called urease. For example, the fungus
Cryptococcus neoformans uses urease to help it spread and colonise.

·      
Sterols: Sterols are an important chemical component of the
cell membranes of plants, animals, and fungi. The compound makes the membranes
more rigid. In mammals, including humans, the principal sterol is cholesterol.
If it is present in high concentrations in the body, it tends to be deposited
in the inner lining of our blood vessels. As the deposits accumulate, they
block the flow of blood, eventually leading to chest pain, heart attack, and/or
stroke.

Role in microorganisms- In fungi, including yeast, the
major sterol is ergosterol. Blocking ergosterol biosynthesis can adversely
affect fungal growth. In fact, many of the most important agents’ humans use to
fight fungal infections are azoles (like fluconazole), which inhibit ergosterol
biosynthesis. Other drugs based on polyenes (such as amphotericin B) bind to
ergosterol in the membranes of fungal cells and disrupt their integrity.

·      
Biosynthesis: Biosynthesis is a process in which living organisms
use chemical reactions to create products for cellular metabolism. It involves
the conversion of substrates into more complex products through a multi-step,
enzyme-catalyzed process. Biosynthesis is also known as anabolism because the
final products are large, complex structures called macromolecules. Some key
features of biosynthesis are: -

Energy-driven- Biosynthesis uses chemical energy, which is generated when a bond is
broken. For example, a terminal high energy phosphate group is hydrolyzed from
ATP to generate energy.

Multi-enzymatic- Multiple enzymes are involved in the process, which catalyze the
reaction by decreasing activation energy.

Controlled- Biosynthesis is controlled at each step.

Includes catabolism and anabolism- Biosynthesis includes both the catabolism and
anabolism (building up and breaking down) of complex molecules.

·      
Way
forward: The protein whose recipe the
ERG25 gene encodes has a known role in sterol biosynthesis. Now it is known it
also confers nickel tolerance — which might involve diverting the protein from
the sterol biosynthesis complex to a different nickel-tolerance complex. A drug
blocking such a diversion between complexes could potentially act as a novel
antifungal agent.