Exhaustive Modeling of Human Milk Oligosaccharide (HMO) Biosynthesis – Nathan Lewis, Lars Bode

[in prepreation]

Human Milk Oligosaccharides (HMOs) are abundant and functionally important components of human milk. A growing body of evidence suggests these glycans have major impacts on the health and development of the breastfed infant. Although they were discovered more than half a century ago, their biosynthesis in the human mammary gland remains minimally characterized. We propose to develop a framework for predicting which glycosyltransferases are involved in HMO biosynthesis and identify candidate structures for poorly characterized HMOs. Our approach constructs and selects candidate models describing HMO biosynthesis, leveraging both metabolic and transcriptomic modeling and data. We will construct a generic metabolic network describing all feasible biosynthetic pathways of 34 potential HMO structures related to the 16 most abundant (>97% by weight) oligosaccharides found in human milk. Through the integration of HMO glycoprofiling and transcriptomics, our mechanistic modeling approach endeavors to identify the most likely HMO structures for uncharacterized HMOs, as well as specifying the association between biosynthetic reactions for those HMOs, and candidate genes for elongation and branching. These results will provide the molecular basis for HMO biosynthesis and thus can be used to guide new strategies for HMO synthesis for academic and nutritional use.