Candida albicans Hexokinase 2 Challenges the Saccharomyces cerevisiae Moonlight Protein Model

Abstract

Survival of the pathogenic yeast Candida albicans depends upon assimilation of fermentable and non-fermentable carbon sources detected in host microenvironments. Among the various carbon sources encountered in a human body, glucose is the primary source of energy. Its effective detection, metabolism and prioritization via glucose repression are primordial for the metabolic adaptation of the pathogen. In C. albicans, glucose phosphorylation is mainly performed by the hexokinase 2 (CaHxk2). In addition, in the presence of glucose, CaHxK2 migrates in the nucleus and contributes to the glucose repression signaling pathway. Based on the known dual function of the Saccharomyces cerevisiae hexokinase 2 (ScHxk2), we intended to explore the impact of both enzymatic and regulatory functions of CaHxk2 on virulence, using a site-directed mutagenesis approach. We show that the conserved aspartate residue at position 210, implicated in the interaction with glucose, is essential for enzymatic and glucose repression functions but also for filamentation and virulence in macrophages. Point mutations and deletion into the N-terminal region known to specifically affect glucose repression in ScHxk2 proved to be ineffective in CaHxk2. These results clearly show that enzymatic and regulatory functions of the hexokinase 2 cannot be unlinked in C. albicans.

Effect of glucose levels on carbon flow rate, antioxidant status, and enzyme activity of yeast during fermentation

“…In the high sugar environment, the yeast's trehalose synthesis gene was also found to be increased, and this is consistent with the results of HK activity in the first 12 h in the 15 g L −1 glucose level group 6,11 . However, the enzyme activity at 36 h was lower than that in the experimental group with 6 and 3 g L −1 glucose levels, respectively, indicating that high glucose levels may inhibit the activity of HK in yeast 57 . In addition, this may be because the intracellular ROS content of yeast tends to be stable after 24 h, the degree of stress decreases, and the yeast reduces the intensity of the trehalose metabolic pathway.…”

“…However, the activity of G6PDH in the 6 and 15 g L −1 glucose groups was significantly lower than that in the 3 g L −1 glucose group at 6 and 12 h, suggesting that yeast utilized carbon resources into other metabolic processes. Another possibility is that HK 2 represses glucose metabolism under high glucose stress, resulting in incongruent prophase hexokinase activity with G6PDH activity at both glucose concentrations 57 . Under high glucose conditions (6 and 15 g L −1 ), yeast G6PDH activity was lower at the initial growth stage, but, by continuously increasing the final 6 and 15 g L −1 glucose level groups at 36 and 24 h, respectively, it was more than the 3% glucose level group.…”

“…Another possibility is that HK 2 represses glucose metabolism under high glucose stress, resulting in incongruent prophase hexokinase activity with G6PDH activity at both glucose concentrations. 57 Under high glucose conditions (6 and 15 g L −1 ), yeast G6PDH activity was lower at the initial growth stage, but, by continuously increasing the final 6 and 15 g L −1 glucose level groups at 36 and 24 h, respectively, it was more than the 3% glucose level group. This is consistent with the strategy of yeast up-regulation of pentose phosphate metabolism genes to cope with stress under high glucose environment.…”

“…6,11 However, the enzyme activity at 36 h was lower than that in the experimental group with 6 and 3 g L −1 glucose levels, respectively, indicating that high glucose levels may inhibit the activity of HK in yeast. 57 In addition, this may be because the intracellular ROS content of yeast tends to be stable after 24 h, the degree of stress decreases, and the yeast reduces the intensity of the trehalose metabolic pathway.…”

Anti-Cariogenic Effects of S. cerevisiae and S. boulardii in S. mutans–C. albicans Cross-Kingdom In Vitro Models

“…Saccharomyces species competed with C. albicans and S. mutans for available nutrients. By utilizing sugars in the environment, Saccharomyces may limit the substrate available for the acid production by C. albicans and potentially reduce the metabolic activities of C. albicans [ 55 ]. The reduced inhibitory effect of Saccharomyces on the growth of S. mutans may be attributed to the slower growth rate of Saccharomyces compared to that of S. mutans .…”