The Batten disease gene product CLN6 is a glycerophosphoglycerol epimerase that establishes S,S-BMP stereochemistry
- 1Stanford University
Abstract
Bis(monoacylglycero)phosphate (BMP), a lysosomal phospholipid essential for lipid catabolism and cholesterol clearance, has a noncanonical S,S glycerol configuration found in no other mammalian phospholipid, a feature necessary for its stability in the lysosome. How cells invert glycerol stereochemistry to build S,S-BMP has remained unexplained since this configuration was discovered five decades ago. Here, we show that the endoplasmic reticulum-resident Batten disease protein CLN6 is a Ca2+-dependent epimerase that isomerizes glycerophosphoglycerol (GPG) from R,S-GPG to S,S-GPG. CLN6-deficient cells, mouse tissues, and patient samples predominantly contain R,S-GPG, S,R-lysophosphatidylglycerol (LPG), and R,S-BMP instead of their S,S counterparts, with a net depletion of BMP. Purified CLN6 catalyzes GPG epimerization in vitro, an activity abolished by a pathogenic substitution in its substrate-binding pocket. Consistently, exogenous S,S-GPG restores BMP synthesis and relieves lipid storage in CLN6-null cells. Our work establishes stereochemical commitment upstream of acylation, placing CLN6, CLN8, and CLN5 in sequence in BMP biosynthesis and unifying the lipid defect across these neurodegenerative disorders.
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BibTeX
@misc{zhu2026batten,
title = {{The Batten disease gene product CLN6 is a glycerophosphoglycerol epimerase that establishes S,S-BMP stereochemistry}},
author = {Z. Zhu and J. Xiong and I. Maaz and M. J. Matrongolo and A. Ghoochani and C. Chilkunda and X. Peng and A. Alur and C. Porsen and A. Schulz and S. Cotman and N. Gomez-Ospina and M. Abu-Remaileh},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.07.757477},
url = {https://www.biorxiv.org/content/10.64898/2026.10.07.757477v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - The Batten disease gene product CLN6 is a glycerophosphoglycerol epimerase that establishes S,S-BMP stereochemistry
AU - Z. Zhu
AU - J. Xiong
AU - I. Maaz
AU - M. J. Matrongolo
AU - A. Ghoochani
AU - C. Chilkunda
AU - X. Peng
AU - A. Alur
AU - C. Porsen
AU - A. Schulz
AU - S. Cotman
AU - N. Gomez-Ospina
AU - M. Abu-Remaileh
PY - 2026
DA - 2026/10/07
PB - bioRxiv
DO - 10.64898/2026.10.07.757477
UR - https://www.biorxiv.org/content/10.64898/2026.10.07.757477v1
AB - Bis(monoacylglycero)phosphate (BMP), a lysosomal phospholipid essential for lipid catabolism and cholesterol clearance, has a noncanonical S,S glycerol configuration found in no other mammalian phospholipid, a feature necessary for its stability in the lysosome. How cells invert glycerol stereochemistry to build S,S-BMP has remained unexplained since this configuration was discovered five decades ago. Here, we show that the endoplasmic reticulum-resident Batten disease protein CLN6 is a Ca2+-dependent epimerase that isomerizes glycerophosphoglycerol (GPG) from R,S-GPG to S,S-GPG. CLN6-deficient cells, mouse tissues, and patient samples predominantly contain R,S-GPG, S,R-lysophosphatidylglycerol (LPG), and R,S-BMP instead of their S,S counterparts, with a net depletion of BMP. Purified CLN6 catalyzes GPG epimerization in vitro, an activity abolished by a pathogenic substitution in its substrate-binding pocket. Consistently, exogenous S,S-GPG restores BMP synthesis and relieves lipid storage in CLN6-null cells. Our work establishes stereochemical commitment upstream of acylation, placing CLN6, CLN8, and CLN5 in sequence in BMP biosynthesis and unifying the lipid defect across these neurodegenerative disorders.
ER -