Brian Kevany | Case Western Reserve University (original) (raw)

Papers by Brian Kevany

Advances in Plant Ethylene Research, 2007

Molecular Genetics and Metabolism, 2019

Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency in alpha-galactosi... more Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency in alpha-galactosidase A (GLA) activity that results in the accumulation of the glycolipid products, globotriaosylceramide (Gb3) and lyso-Gb3 in the lysosome. Disease manifestations include frequent bouts of peripheral neurotrophic pain, angiokeratomas, reduced sweat production, corneal dystrophy, cardiomyopathy, renal insufficiency and cerebrovascular disease, which result in reduced lifespan in Fabry patients. While males are affected more severely due to the mutations in the GLA gene, female patients are also frequently symptomatic and are often misdiagnosed. Enzyme replacement therapy (ERT) is currently the only FDA-approved therapy to treat Fabry and requires bi-weekly injections of relatively large quantities of recombinant protein. While ERT reduces the accumulation of Gb3 in the heart, kidney and vasculature it fails to completely treat all symptoms of Fabry, primarily due to its inability to effi...

Pompe disease is a lysosomal storage disorder caused by a deficiency in acid alpha-glucosidase (G... more Pompe disease is a lysosomal storage disorder caused by a deficiency in acid alpha-glucosidase (GAA) activity that results in the accumulation of glycogen in the lysosome. The disease presents as a form of muscular dystrophy which primarily affects both smooth and striated musculature as well as the central nervous system (CNS), with early mortality. Enzyme replacement therapy (ERT) is currently the only FDA-approved therapy to treat Pompe and requires bi-weekly injections of relatively large quantities of recombinant protein. While ERT significantly reduces the mortality rate of infantile Pompe patients, who typically die by the age of two without therapy, it fails to completely ameliorate all symptoms of Pompe, primarily due to its inability to efficiently enter the CNS and resulting immune responses to the GAA protein. Gene therapy strategies have been investigated and while many show great promise in correcting the glycogen accumulation and other symptoms of Pompe, most have suf...

of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillm... more of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy ROLE OF MEMBERS OF THE TOMATO ETHYLENE RECEPTOR FAMILY IN DETERMINING THE TIMING OF RIPENING By Brian Michael Kevany December 2007 Chair: Harry John Klee Major: Plant Molecular and Cellular Biology Tomatoes are an economically important crop and a significant dietary source of important phytochemicals, such as carotenoids and flavonoids. While it has been known for many years that the plant hormone ethylene is essential for ripening of climacteric fruits, its role in fruit growth and maturation is much less understood. In an attempt to better understand tomato fruit ripening we utilized both biotechnology and traditional breeding strategies. The multigene ethylene receptor family has been shown to negatively regulate ethylene signal transduction and suppress ethylene responses. Here, we demonstrate that a reduction in the lev...

A phytohormone (plant hormone) that is an important signaling molecule involved in many plant pro... more A phytohormone (plant hormone) that is an important signaling molecule involved in many plant proces…

Molecular Genetics and Metabolism

The Journal of biological chemistry, Dec 4, 2017

One of the major biological functions of the retinal pigmented epithelium (RPE) is the clearance ... more One of the major biological functions of the retinal pigmented epithelium (RPE) is the clearance of shed photoreceptor outer segments (POS) through a multistep process resembling phagocytosis. RPE phagocytosis helps maintain the viability of photoreceptors that otherwise could succumb to the high metabolic flux and photo-oxidative stress associated with visual processing. The regulatory mechanisms underlying phagocytosis in the RPE are not fully understood, although dysfunction of this process contributes to the pathogenesis of multiple human retinal degenerative disorders, including age-related macular degeneration. Here, we present an integrated transcriptomic, proteomic, and phosphoproteomic analysis of phagocytosing RPE cells, utilizing three different experimental models: human-derived RPE-like cell line, ARPE-19, cultured murine primary RPE cells, and RPE samples from live mice. Our combined results indicated that early stages of phagocytosis in the RPE are mainly characterize...

Journal of Biological Chemistry

Accumulation of bis-retinoids in the retinal pigmented epithelium (RPE) is a hallmark of aging an... more Accumulation of bis-retinoids in the retinal pigmented epithelium (RPE) is a hallmark of aging and retinal disorders such as Stargardt disease and age-related macular degeneration. These aberrant fluorescent condensation products, including di-retinoid-pyridinium-ethanolamine (A2E), are thought to be transferred to RPE cells primarily through phagocytosis of the photoreceptor outer segments. However, we observed by twophoton microscopy that mouse retinas incapable of phagocytosis due to a deficiency of the c-Mer proto-oncogene tyrosine kinase (Mertk) nonetheless contained fluorescent retinoid condensation material in their RPE. Primary RPE cells from Mertk ؊/؊ mice also accumulated fluorescent products in vitro. Finally, quantification of A2E demonstrated the acquisition of retinal condensation products in Mertk ؊/؊ mouse RPE prior to retinal degeneration. In these mice, we identified activated microglial cells that likely were recruited to transport A2E-like condensation products to the RPE and dispose of the dying photoreceptor cells. These observations demonstrate a novel transport mechanism between photoreceptor cells and RPE that does not involve canonical Mertk-dependent phagocytosis.

The phytohormone ethylene is essential for ripening of climacteric fruits such as tomato. While m... more The phytohormone ethylene is essential for ripening of climacteric fruits such as tomato. While many of the genes responsible for ethylene synthesis and percep- tion have been identiWed, the regulatory network control- ling autocatalytic climacteric ethylene synthesis is not well understood. In order to better understand the regulation of ripening-associated ethylene, we have exploited the genetic variation within Solanum Sect.

ChemInform, 2009

The biosynthetic pathways to polyketide-derived polycyclic ethers, in bacteria, plants and marine... more The biosynthetic pathways to polyketide-derived polycyclic ethers, in bacteria, plants and marine organisms, have, until now, tended to be considered separately. The purpose of this article is to provide an integrated review of the common mechanistic aspects of polyether biosynthesis from these diverse sources. In particular, the focus will be on the proposed mechanisms of oxidative cyclisation, as well as on the known differences in polyketide chain construction between the terrestrial and marine polyethers.

PloS one, 2014

We have previously shown that the acyl transferase domain of ZmaA (ZmaA-AT) is involved in the bi... more We have previously shown that the acyl transferase domain of ZmaA (ZmaA-AT) is involved in the biosynthesis of the aminopolyol polyketide/nonribosomal peptide hybrid molecule zwittermicin A from cereus UW85, and that it specifically recognizes the precursor hydroxymalonyl-acyl carrier protein (ACP) and transfers the hydroxymalonyl extender unit to a downstream second ACP via a transacylated AT domain intermediate. We now present the X-ray crystal structure of ZmaA-AT at a resolution of 1.7 Å. The structure shows a patch of solvent-exposed hydrophobic residues in the area where the AT is proposed to interact with the precursor ACP. We addressed the significance of the AT/ACP interaction in precursor specificity of the AT by testing whether malonyl- or methylmalonyl-ACP can be recognized by ZmaA-AT. We found that the ACP itself biases extender unit selection. Until now, structural information for ATs has been limited to ATs specific for the CoA-linked precursors malonyl-CoA and (2S)-m...

The Plant Journal, 2007

Fruit ripening in tomato requires the coordination of both developmental cues and the phytohormon... more Fruit ripening in tomato requires the coordination of both developmental cues and the phytohormone ethylene. The multigene ethylene receptor family has been shown to negatively regulate ethylene signal transduction and suppress ethylene responses. Here we demonstrate that reduction in the levels of either of two family members, LeETR4 or LeETR6, causes an early-ripening phenotype. We provide evidence that the receptors are rapidly degraded in the presence of ethylene, and that degradation probably occurs through the 26S proteasome-dependent pathway. Ethylene exposure of immature fruits causes a reduction in the amount of receptor protein and earlier ripening. The results are consistent with a model in which receptor levels modulate timing of the onset of fruit ripening by measuring cumulative ethylene exposure.

Plant Biotechnology Journal, 2008

Tomato is an economically important crop and a significant dietary source of important phytochemi... more Tomato is an economically important crop and a significant dietary source of important phytochemicals, such as carotenoids and flavonoids. Although it has been known for many years that the plant hormone ethylene is essential for the ripening of climacteric fruits, its role in fruit growth and maturation is much less well understood. In this study, data are presented which indicate that fruit-specific suppression of the ethylene receptor LeETR4 causes early ripening, whereas fruit size, yield and flavour-related chemical composition are largely unchanged. Early fruit ripening is a highly desirable and valuable trait, and the approach demonstrated here should be applicable to any fruit species requiring ethylene to ripen. These results demonstrate that ethylene receptors probably act as biological clocks regulating the onset of tomato fruit ripening.