Repression of L-methionine dependent fungal growth by L-penicillamine - Publication - Bridge of Knowledge

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Repression of L-methionine dependent fungal growth by L-penicillamine

Abstract

Invasive fungal mycoses are a serious threat to human health, especially to immunosuppressed patients. A significant role of fungal infections in the death toll of COVID19 is also reported. Current antifungal therapies do not appear to be sufficient, therefore, identification of novel molecular targets is highly desirable. Enzymes participating in the biosynthesis pathways of essential amino acids like L-methionine (L-Met) seem to be promising. There are no enzyme counterparts in human cells which limits possibility of serious side effects appearance. Deletion of genes encoding relevant enzymes in this pathway led mostly to L-Met auxotrophy and reduced virulence of the pathogens in animal models of infection. The concentration of L-Met in the blood serum is ~ 30 μM and is probably too low to compensate for the effect of blocking the activity of fungal enzymes. We have examined L-homoserine O-acetyltransferase (Met2p) from Candida albicans, which catalyzes the first step in L-Met biosynthesis pathway and identified L-penicillamine (L-PEN) as its inhibitor. Unlike the first enzyme of the biosynthetic pathway in bacterial cells, a fungal enzyme is not inhibited by LMet. L-PEN’s antifungal effect could be observed mostly in C. glabrata and S. cerevisiae strains in the absence of L-Met in medium, proving that unlike most fungal species, C. glabrata and S. cerevisiae possess only one route leading to the biosynthesis of L-cysteine, which serves as a precursor for the L-Met production. In C. albicans, a bridge role between O-acetyl-L-serine and the transsulfuration pathway plays the Str2p enzyme that catalyzes the transformation of L-cysteine to L-Met via L-cystathionine. This route enables overcoming the auxotrophy and increases the adaptive capacity of this opportunistic pathogen. Our results show that to completely block the L-Met biosynthetic pathway, simultaneous inhibition of Met15p and Str2p is needed. The same substrate usage by these enzymes makes it probable.

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Details

Category:
Articles
Type:
suplement w czasopiśmie
Published in:
FEBS Open Bio no. 12,
ISSN: 2211-5463
Language:
English
Publication year:
2022
DOI:
Digital Object Identifier (open in new tab) 10.1002/2211-5463.13440
Sources of funding:
Verified by:
Gdańsk University of Technology

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