Science with Sandra and Dr. Rodrigo Starosta

Hello and Welcome to Science with Sandra!

For this edition of Science with Sandra I would like to share some information about fucose to help you have a better understanding in preparation for the upcoming clinical trial.

Fucose, what is it?

Fucose is a monosaccharide that is found in a large variety of different organisms, although usually in very small quantities. L-Fucose (which is the active form of fucose), is a dietary sugar that can play important roles in cellular biology. 

L-Fucose

In mammals, fucose is incorporated into proteins and lipids through a process called fucosylation, which is an important part of a series of reactions that are collectively called glycosylation.

Glycosylation is process that involves the addition of molecules made of chains of carbohydrates (glycans), to different biomolecules such as proteins and lipids. In eukaryotic cells, this process is key in protein folding, protein stability and cell signaling. Glycosylation is divided into two main categories: N-linked and O-linked glycosylation. N-linked glycosylation involves the glycan or carbohydrate being connected to the protein though a nitrogen atom of the amino acid asparagine. O-linked glycosylation, involves the attachment of the carbohydrate to the oxygen atom of the amino acid serine or threonine. This process of glycosylation using fucose is called fucosylation. 

Use

Fucose is added to proteins or lipids by enzymes called fucosyltransferases, and the addition of fucose by these enzymes plays an important role in different biological systems. Fucose containing glycans in mammals are important in development, immune responses, human disease and as components of the blood groups and cells in the immune system.

The first step of fucosylation involves taking L-fucose from either endogenous (internal) or exogenous (external) sources. Endogenous L-fucose is derived from intracellular recycling of glycosylated proteins, while exogenous fucose comes from a variety of plants. L-fucose is found in potato’s cell wall, cassava tuber, kiwi, and thale cress and in different types of seeds including soybeans. Additionally, it has been reported to be enriched at significantly higher amounts in different species of seaweed in the form of sulfated L-fucose polymers also known as fucoidan. 

In order for L-fucose to be used in protein fucosylation, L-fucose needs to be processed and turned into GDP-fucose (“activated fucose”). Intracellular levels of GDP-fucose are maintained by two different pathways, the salvage pathway and the de novo pathway. The de novo pathway produces 80-90% of cellular GDP-fucose under normal circumstances, and uses another activated sugar, GDP-mannose, as a substrate, while the salvage pathway requires exogenous or recycled L-fucose to produce fucosylated proteins. Once GDP-fucose is produced, it is used to produce fucosylated N- and O-glycans by enzymes called fucosyltransferases. Fucose is usually the last monosaccharide to be added to a glycan chain.

What is the relationship with Glut1 Deficiency?

A while back, Dr. Matthew Gentry, our science advisor and a leading expert in glycogen and glycogen storage diseases, was interested in learning more about glycogen levels in Glut1 Deficiency and got mice from Dr. Juan Pascual. He learned that glycogen is significantly reduced in the brains of Glut1 deficient mice, which means that the brain glucose reserves are significantly impacted. He also learned that the brains of these mice are low in some of the sugars involved in glycosylation, including fucose. Around that time, Dr. Hudson Freeze, a leading expert on Congenital Disorders of Glycosylation (or CDG’s), reached out to Dr. Gentry about a high impact paper his team had published about glycogen, and Dr. Freeze shared that his lab had recently discovered that Glut1 was also transporting fucose in addition to glucose, which led to the publication “GLUT1 is a highly efficient L-fucose transporter”.

As a result, Dr. Gentry, Dr. Freeze, Dr. Pascual, and Dr. Ramon Sun collaborated on a project to test L-fucose supplementation in Glut1 Deficient mice and the G1DF provided some funding. The treatment was conducted for 10 days with daily supplementation of healthy mice and Glut1 deficient mice. The results showed improvements in motor skills of Glut1 Deficient mice as well as increased brain glycogen storage and glycosylation.

This work has been presented at different conferences and with other rare disease communities such as the Congenital Disorders of Glycosylation or CDG community. One of the physician-researchers in this community, Dr. Rodrigo Starosta, heard one of the presentations and was really interested in exploring the possibility of using L-fucose to treat Glut1 Deficiency. He is a geneticist and metabolic specialist at Oregon Heath and Science University and has experience treating patients with a CDG disorder (SLC35C1-CDG) using fucose. Dr. Starosta has been working together with Dr. Pascual, Dr. Gentry and Dr. Freeze to plan the upcoming fucose clinical trial, which is being funded by the Glut1 Deficiency Foundation thanks to its community of supporters.

The G1DF will organize a virtual gathering where Dr. Starosta will be the guest speaker and where he will share more information about the trial, what to expect, and how to participate. This will be planned when the details are more concrete and have been fully approved by his Institutional Review Board.

You can send any questions you have about the trial to me at [email protected] and I will send them to him ahead of the meeting so he can respond live.

I thank Dr. Starosta for reviewing this post and for his interest in helping our community to reach a brighter future!