Candida albicans Hom6 is a homoserine dehydrogenase involved in protein synthesis and cell adhesion

Tsai, Pei-Wen; Chien, Chu‐Yang; Yeh, Ying-Chieh; Tung, Luh; Chen, Hsueh‐Fen; Lan, Chung-Yu

doi:10.1016/j.jmii.2016.03.001

Cited by 8 publications

(8 citation statements)

References 37 publications

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“…This scan confirmed that AnHSD is a member of the homoserine dehydrogenase lacking ACT domain superfamily (IPR022697), containing an N-terminal NAD-binding homoserine dehydrogenase domain (IPR00001342) (amino acids [aa] 10 to 150), and an homoserine dehydrogenase domain (IPR005106) (aa 158 to 336).In addition, to identify and compare the conserved residues between AnHSD and other HSDs in more details, we retrieved 21 representative sequences from various species for sequence alignment analysis. Multiple sequence alignment revealed the conserved sequence motifs G-X-G-X-X-G/A/N was reported to be important for NAD(P) + binding located at N-terminal (Fig.1A) (15), and the highly conserved sequences between 180 and 210 amino acids that were important for the catalytic activity of AnHSD (Fig.1B) (15–17).…”

Section: Resultsmentioning

confidence: 99%

“…A BLAST-P analysis 10 to 150), and an homoserine dehydrogenase domain (IPR005106) (aa 158 to 336).In addition, to identify and compare the conserved residues between AnHSD and other HSDs in more details, we retrieved 21 representative sequences from various species for sequence alignment analysis. Multiple sequence alignment revealed the conserved sequence motifs G-X-G-X-X-G/A/N was reported to be important for NAD(P) + binding located at N-terminal ( Fig.1A) (15), and the highly conserved sequences between and amino acids that were important for the catalytic activity of AnHSD ( Fig.1B) (15)(16)(17). Compared with the control group and the experimental group showed a peak of L-ASA ( Fig…”

Section: Identification and Cloning Of Potential Homoserine Dehydrogementioning

confidence: 99%

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Characterization of a Novel Type Homoserine Dehydrogenase Only with High Oxidation Activity fromArthrobacter nicotinovorans

Liang¹,

Deng²,

Bai

et al. 2021

Preprint

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Homoserine dehydrogenase (HSD) is a key enzyme in the synthesis pathway of the aspartate family of amino acids. HSD can catalyze the reversible reaction of L-aspartate-β-semialdehyde (L-ASA) to L-homoserine (L-Hse). In direct contrast, growth characteristic studies of some bacterial such as Arthrobacter nicotinovorans showed that the bacterium could grow well in medium with L-homoserine as sole carbon, nitrogen and energy source, but the genes responsible for the degradation of L-Hse remain unknown. Based on the function and sequence analysis of HSD, one putative homoserine dehydrogenase from A.nicotinovorans was named AnHSD, which was different from those HSDs that from the aspartic acid metabolic pathway, might be responsible for the degradation of L-Hse. Surprisingly, the analysis showed that the purified AnHSD exhibited specific L-Hse oxidation activity without reducing activity. At pH 10.0 and 40 oC, The Km and Kcat of AnHSD was 6.30 ± 1.03 mM and 462.71 s-1, respectively. AnHSD was partiality for NAD+ cofactor, as well as insensitive to feedback inhibition of downstream amino acids of aspartic acid family. The physiological role of AnHSD in A.nicotinovorans is discussed. These findings provide a novel insight for a better understanding of an alternative genetic pathway for L-Hse catabolism which was dominated by the novel HSD.

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Section: Resultsmentioning

confidence: 99%

Section: Identification and Cloning Of Potential Homoserine Dehydrogementioning

confidence: 99%

Characterization of a Novel Type Homoserine Dehydrogenase Only with High Oxidation Activity fromArthrobacter nicotinovorans

Liang¹,

Deng²,

Bai

et al. 2021

Preprint

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“…This enzyme catalyzes the third reversible reaction in this pathway producing L-homoserine 20,32 . Notably, this "sulfur assimilation pathway" is present in the fungal kingdom, but not in humans 33,34 . HCS and SDH catalyze the first and last step of the α-aminoadipate pathway that results in L-lysine biosynthesis.…”

Section: Discussionmentioning

confidence: 99%

New Therapeutic Candidates for the Treatment of Malassezia pachydermatis -Associated Infections

Sastoque

Triana

Ehemann

et al. 2020

Sci Rep

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the opportunistic pathogen Malassezia pachydermatis causes bloodstream infections in preterm infants or individuals with immunodeficiency disorders and has been associated with a broad spectrum of diseases in animals such as seborrheic dermatitis, external otitis and fungemia. The current approaches to treat these infections are failing as a consequence of their adverse effects, changes in susceptibility and antifungal resistance. Thus, the identification of novel therapeutic targets against M. pachydermatis infections are highly relevant. Here, Gene Essentiality Analysis and Flux Variability Analysis was applied to a previously reported M. pachydermatis metabolic network to identify enzymes that, when absent, negatively affect biomass production. Three novel therapeutic targets (i.e., homoserine dehydrogenase (MpHSD), homocitrate synthase (MpHCS) and saccharopine dehydrogenase (MpSDH)) were identified that are absent in humans. Notably, L-lysine was shown to be an inhibitor of the enzymatic activity of MpHCS and MpSDH at concentrations of 1 mM and 75 mM, respectively, while L-threonine (1 mM) inhibited MpHSD. Interestingly, L-lysine was also shown to inhibit M. pachydermatis growth during in vitro assays with reference strains and canine isolates, while it had a negligible cytotoxic activity on HEKa cells. Together, our findings form the bases for the development of novel treatments against M. pachydermatis infections. The yeast M. pachydermatis is part of the skin microbiota of domestic and wild animals and behaves as an opportunistic pathogen causing external otitis and seborrheic dermatitis in dogs and cats. Particular conditions such as the presence of lipid-rich microenvironments, a local imbalance of the natural microbiota and altered immune states favor these infections 1. Dermatologic infections caused by M. pachydermatis often exhibit a chronic (recurrent) course and their treatment can be complicated due to the ability of this yeast to form biofilms 1. In addition, M. pachydermatis causes bloodstream infections in preterm infants or in individuals with immunodeficiency disorders. These infections are related to contamination of medical devices such as catheters, the transmission through medical staff and the administration of lipids through intravenous way 2,3. Recently, several factors contributing to M. pachydermatis virulence have been determined, which include the production of proteinases, phospholipases, hyaluronidases, and chondroitin-sulfatases 4. Currently, five classes of antifungal agents are used orally, topically or intravenously for the treatment of fungal infections. The first class is formed by the azoles (ketoconazole, itraconazole, clotrimazole, miconazole, and

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“…It was reported that C. albicans hom6Δ cells were hypersensitive to hygromycin B, thus suggesting Hom6p involvement in protein glycosylation (Tsai et al 2017), since previously a correlation between defects in protein glycosylation and hygromycin B sensitivity of S. cerevisiae was found (Dean 1995). Furthermore, it was revealed by proteomic studies that Hom6p is localized in both cytosolic and cell wall fractions of C. albicans (Ebanks et al 2006;Montserrat Martínez-Gomariz et al 2009;Tsai et al 2017). Additionally, novel inhibitors of homoserine dehydrogenase were found among 4-methoxy-naphthalene derivatives (Bagatin et al 2019).…”

Section: Biosynthesis Pathways Of Amino Acids Of the Aspartate Familymentioning

confidence: 99%

Molecular targets for antifungals in amino acid and protein biosynthetic pathways

Kuplińska

Rząd

2021

Amino Acids

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Fungi cause death of over 1.5 million people every year, while cutaneous mycoses are among the most common infections in the world. Mycoses vary greatly in severity, there are long-term skin (ringworm), nail or hair infections (tinea capitis), recurrent like vaginal candidiasis or severe, life-threatening systemic, multiorgan infections. In the last few years, increasing importance is attached to the health and economic problems caused by fungal pathogens. There is a growing need for improvement of the availability of antifungal drugs, decreasing their prices and reducing side effects. Searching for novel approaches in this respect, amino acid and protein biosynthesis pathways appear to be competitive. The route that leads from amino acid biosynthesis to protein folding and its activation is rich in enzymes that are descriptive of fungi. Blocking the action of those enzymes often leads to avirulence or growth inhibition. In this review, we want to trace the principal processes of fungi vitality. We present the data of genes encoding enzymes involved in amino acid and protein biosynthesis, potential molecular targets in antifungal chemotherapy, and describe the impact of inhibitors on fungal organisms.

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Candida albicans Hom6 is a homoserine dehydrogenase involved in protein synthesis and cell adhesion

Abstract: Given that there is no Hom6 homologue in mammalian cells, our results provided an important foundation for future development of new antifungal drugs.

Cited by 8 publications

References 37 publications

Characterization of a Novel Type Homoserine Dehydrogenase Only with High Oxidation Activity fromArthrobacter nicotinovorans

Characterization of a Novel Type Homoserine Dehydrogenase Only with High Oxidation Activity fromArthrobacter nicotinovorans

New Therapeutic Candidates for the Treatment of Malassezia pachydermatis -Associated Infections

Molecular targets for antifungals in amino acid and protein biosynthetic pathways

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