The Development of LAT1 Efflux Agonists as Mechanistic Probes of Cellular Amino Acid Stress.

Amino acid restriction induces cellular stress and cells often respond via the induction of autophagy. Autophagy or 'self-eating' enables the recycling of proteins and provides the essential amino acids needed for cell survival. Of the naturally occurring amino acids, methionine restriction has pleiotropic effects on cells because methionine also contributes to the intracellular methyl pools required for epigenetic controls as well as polyamine biosynthesis. In this report, we describe the chemical synthesis of four diastereomers of a methionine depletion agent and demonstrate how controlled methionine efflux from cells significantly reduces intracellular methionine, S-adenosylmethionine (SAM), S-adenosyl homocysteine (SAH), and polyamine levels. We also demonstrate that human pancreatic cancer cells respond via a lipid signaling pathway to induce autophagy. The methionine depletion agent causes the large amino acid transporter 1 (LAT1) to preferentially work in reverse and export the cell's methionine (and leucine) stores. The four diastereomers of the lead methionine/leucine depletion agent were synthesized and evaluated for their ability to (a) efflux 3H-leucine from cells, (b) dock to LAT1 in silico, (c) modulate intracellular SAM, SAH, and phosphatidylethanolamine (PE) pools, and (d) induce the formation of the autophagy-associated LC3-II marker. The ability to modulate the intracellular concentration of methionine regardless of exogenous methionine supply provides new molecular tools to better understand cancer response pathways. This information can then be used to design improved therapeutics that target downstream methionine-dependent processes like polyamines.

Bullous Pemphigoid Complicated by Sepsis.

Patients with bullous pemphigoid face many challenges when managing their disorder, one of which is balancing medication with their ailments. Because the patient population with bullous pemphigoid are primarily elderly, the current first-line treatment of corticosteroids tends to increase their rates of morbidity and mortality. During the acute process of the disease, providers must also consider the increased chance of infections caused by the opening in the skin. These patient cases are often complicated further by secondary symptoms such as pruritis and pain. Here we present a case in which we provided care to a 38-year-old female with a history of bullous pemphigoid and multiple medical problems who presented to the emergency department with nausea, vomiting, fevers, abdominal pain, and blisters on her forearm. Due to concern for sepsis and her past failure of outpatient therapy, the patient was hospitalized and treated for her possible infection, bullous pemphigoid, nausea, and pain.