# Structural and Functional Studies of Human Serine Palmitoyltransferase Complexes

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2021 · $367,975

## Abstract

PROJECT SUMMARY
Sphingolipids not only are essential structural components of eukaryotic membranes, but also function as
signaling molecules and mediate many biological processes. Defects in sphingolipid metabolism are often
associated with cancers and neurodegenerative diseases. Despite the importance of bioactive sphingolipids,
molecular mechanisms of their biogenesis and homeostasis remain poorly understood. In humans, the first and
rate-limiting step of sphingolipid biosynthesis is catalyzed by the serine palmitoyltransferase complex, which
consists of catalytic component SPTLCs and regulatory components ssSPT and ORMDL. This key enzyme
complex also senses cellular sphingolipid levels to adjust sphingolipid production accordingly, making it a
critical feedback regulator in maintaining sphingolipid homeostasis. Human mutations in the complex lead to
hereditary sensory neuropathy and early-onset amyotrophic lateral sclerosis. However, the mechanism and
regulation of the complex are unclear. We propose to elucidate 1) the substrate recognition and catalytic
reaction of the complex, 2) the role of regulatory components, and 3) the sphingolipid-sensing and feedback
mechanism. To accomplish these aims, we will combine high-resolution structural biology, biochemistry, and
biophysics to provide structural and mechanistic insights into sphingolipid biogenesis and homeostasis
governed by the serine palmitoyltransferase complex. Our proposed studies will greatly advance our
understanding of sphingolipid biology by uncovering the molecular basis of an essential step in sphingolipid
biogenesis and a mechanism of sphingolipid homeostasis.

## Key facts

- **NIH application ID:** 10277991
- **Project number:** 1R01GM143282-01
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Chia-Hsueh Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $367,975
- **Award type:** 1
- **Project period:** 2021-08-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10277991

## Citation

> US National Institutes of Health, RePORTER application 10277991, Structural and Functional Studies of Human Serine Palmitoyltransferase Complexes (1R01GM143282-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10277991. Licensed CC0.

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