Biology subjects

Horvath, M. P.

Publications and source records attributed to Horvath, M. P..

3 recordsLinked to original sources

bioRxiv2025

Mechanism of Lutein to meso-Zeaxanthin Isomerization by RPE65 Catalysis

The macular pigments lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ) protect the human retina from light and oxidative stress. While L and Z are abundant in the human diet, MZ is nearly absent. We previously demonstrated MZ is derived from L in chicken embryos precisely timed with expression of RPE65. Herein, we show that RPE65 from mouse, an animal that does not concentrate MZ in the eye, catalyzes L to MZ isomerization similarly as found for RPE65 from chicken and human, when expressed in cultured cells. Co-expression with xanthophyll-binding proteins had no impact on MZ yield. L and MZ both fit deep into the tunnel accessing the non-heme iron center, with strain evident for the 3R,6R {varepsilon} ring of L. Interestingly, a negatively charged Glu148, found along substrate tunnel, highly conserved among carotenoid cleavage dioxygenases, and which is critical for eye health, could be replaced by a neutral, isosteric residue (Gln) without impacting MZ yield. We propose that L to MZ isomerization proceeds by a neutral, radical transition state that differs from the carbocation encountered during retinoid isomerization. These findings extend our mechanistic understanding for macular carotenoid metabolism and should be considered when developing therapeutic interventions that act via RPE65.

biochemistry↗

bioRxiv2025

Persistent trade-offs balance competition and colonization across centuries

Microbial competition drives rapid adaptation, often forcing organisms to specialize in new ecological niches. Adaptations that improve competitive ability can reduce performance in other environments creating trade-offs. Whether such trade-offs persist in nature--or are eroded as lineages adapt through compensatory changes--remains largely unknown. Here we show that a trade-off between competitive ability and host colonization has been stably maintained in natural Pseudomonas populations for centuries. Wild plant-pathogenic Pseudomonas compete using tailocins--phage-derived molecular weapons that bind to specific cell-surface receptors. Genomic surveys and functional assays reveal that the most broadly lethal tailocins remain rare--while the tailocins production increases competitive killing, it also compromises plant colonization. We determine that the polymorphisms behind this trade-off are not transient -- historical genomes spanning two centuries show that the trade-off has been maintained for at least 10-10 generations. Our results demonstrate that, in natural populations, a trade-off between competition and pathogenicity is fundamental and not easily overcome. SignificanceWhen a microbe colonizes a host, it must both establish infection and outcompete other organisms. Short-term experiments show that gains in competitive ability can reduce colonization, creating trade-offs, but whether microbes resolve these conflicts over long evolutionary timescales is unknown. We show that a trade-off between competitive killing and host colonization has been stably maintained for centuries in natural Pseudomonas populations infecting Arabidopsis thaliana. Tailocins--phage-derived weapons--provide strong competitive advantages, yet their production reduces colonization success, explaining why the most broadly lethal variants remain rare. Genomic surveys and historical genomes spanning two centuries reveal that the polymorphisms underlying this trade-off have persisted across 10-10 generations. Understanding such long-lived constraints can inform antimicrobial strategies that exploit evolutionary trade-offs.

evolutionary biology↗

bioRxiv2023

Metagenome mining and functional analysis reveal oxidized guanine DNA repair at the Lost City Hydrothermal Field

The GO DNA repair system protects against GC [->] TA mutations by finding and removing oxidized guanine. The system is mechanistically well understood but its origins are unknown. We searched metagenomes and abundantly found the genes encoding GO DNA repair at the Lost City Hydrothermal Field (LCHF). We recombinantly expressed the final enzyme in the system to show MutY homologs function to suppress mutations. Microbes at the LCHF thrive without sunlight, fueled by the products of geochemical transformations of seafloor rocks, under conditions believed to resemble a young Earth. High levels of the reductant H2 and low levels of O2 in this environment raise the question, why are resident microbes equipped to repair damage caused by oxidative stress? MutY genes could be assigned to metagenome assembled genomes (MAGs), and thereby associate GO DNA repair with metabolic pathways that generate reactive oxygen, nitrogen and sulfur species. Our results indicate that cell-based life was under evolutionary pressure to cope with oxidized guanine well before O2 levels rose following the great oxidation event.

evolutionary biology↗