Researchers at Case Western Reserve University School of Medicine have uncovered the mechanism¹ that enables the enzyme² Lecithin: retinol acyltransferase (LRAT) to store vitamin A--a process that is indispensable for vision. "Without this information, our knowledge was inadequate³ to understand the molecular⁴ mechanisms⁵ of blindness caused by mutations in the enzyme," said Marcin Golczak, assistant professor of pharmacology at Case Western Reserve and an author of the study.

 

The researchers hope the new information will be used to design small molecule⁷ therapies for degenerative eye diseases. The same enzymatic⁹ activity of LRAT that allows specific cells to absorb vitamin A can be used to transport small molecule drugs to the eye. These drugs would accumulate in eye tissue, lowering the effective dose and reducing risk of systemic side effects.

 

Their work is published in the journal Nature Chemical Biology.

 

Golczak, medical student Avery E. Sears, pharmacology instructor¹⁰ Philip D. Kiser and pharmacology chair Krzysztof Palczewski compared the function of LRAT and closely related enzymes¹¹ that belong to N1pC/P60 family. They found that small variations in the protein sequences determine the substrate specificity--the substances on which the enzymes act--and thus govern physiological¹² functions of these enzymes.

 

LRAT regulates cellular¹³ uptake of vitamin A by helping¹⁴ convert it to a usable form called retinyl ester. Retinyl ester is essential for our eyes to function. Consequently, lack of LRAT leads to vitamin A deficiency and blindness.

 

Unlike LRAT, a close relative, HRAS-like tumor¹⁵ suppressor 3, referred to as HRASLS3, does not process vitamin A, but is involved in regulation of triglycerides breakdown¹⁶ in white fat cells. Triglycerides provide an energy source for body tissues. But excess accumulation leads to obesity¹⁷ and related metabolic¹⁸ syndrome¹⁹, increasing the risk of heart disease, diabetes²⁰ and other health problems.

 

Mice lacking HRASLS3 gained no weight when fed high-calorie diets--even mice that were genetically²¹ engineered to be obese²² and lacking leptin, the hormone²³ that signals mammals when they've eaten enough food.

 

The functions of these enzymes were known, but until now, there has been little understood about what enables the close relatives to go about their different jobs. The researchers looked at how LRAT is different from the rest of its protein family.

 

"Evolution of enzymatic activities via gene⁸ duplication, mutation⁶ and selection has led to the present diversity of metabolic capabilities," Golczak said. "Our studies explain what modification²⁴ in the cellular enzymatic machinery²⁵ enables vertebrates to efficiently²⁶ take up and store excess vitamin A."

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