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Defining Human Cytochrome P450 7B1 Structure and Function to Understand Spastic Paraplegia Type 5 Disease

Award Number: F31GM155958
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2025
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Defining Human Cytochrome P450 7B1 Structure and Function to Understand Spastic Paraplegia Type 5 Disease - PROPOSAL ABSTRACT Human membrane cytochrome P450 7B1 (CYP7B1) is a steroidogenic heme-containing monooxygenase primarily expressed in liver and brain. CYP7B1 performs 7α-hydroxylation of 25- and 27-hydroxycholesterol to ultimately generate the primary bile acid chenodeoxycholic acid. Biallelic, missense mutations in CYP7B1 can result in the loss of enzymatic function, causing accumulation of 25-hydroxycholesterol and 27-hydroxycholesterol in plasma and 27-hydroxycholesterol in cerebrospinal fluid. These mutations cause a neurological disorder called spastic paraplegia type 5 (SPG5). SPG5 patients suffer from severe progressive spasticity and weakness of the lower limbs due to the degeneration of their lower motor neurons. To date, there are no curative or disease-modifying treatments available for SPG5 patients, and little is known about how CYP7B1 mutations affect protein function and cause disease. This proposal takes a first step toward addressing this knowledge gap by determining wild type CYP7B1 interactions with its substrates and functional defects produced by common SPG5-causing missense mutations. First, a CYP7B1 X-ray structure will identify active site residues involved in binding 25-hydroxycholesterol and 27-hydroxycholesterol. Preliminary investment has yielded highly purified CYP7B1 protein and 2-dimensional plate crystals with 25- hydroxycholesterol, substantial progress towards an X-ray structure. Second, common SPG5-causing missense mutations will be assessed to determine protein folding and heme incorporation, ligand binding capacity, and product formation to understand mutation impact and severity. Preliminary results reveal a variety of unpredicted effects, including issues with folding and heme incorporation and reduced substrate binding capacity. Overall, this information will provide the first human CYP7B1 protein structure, permitting identification of active site residues involved in normal substrate binding and will provide the biological roles of CYP7B1 mutants commonly known to cause SPG5. This characterization is a first step in advancing our molecular understanding of SPG5 defects, and has the potential to support future therapeutic treatments for SPG5 patients.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $49,538 )
2026	2026	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	2	1/7/2026	NON-COMPETING CONTINUATION	$49,538
														Subtotal = $49,538

Issue Date FY: 2025 ( Subtotal = $48,974 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	001	1	11/13/2024	NEW	$0
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	1	11/13/2024	NEW	$48,974
														Subtotal = $48,974

Grand Total All Awards = $98,512

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Defining Human Cytochrome P450 7B1 Structure and Function to Understand Spastic Paraplegia Type 5 Disease

Award Number: F31GM155958

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2025

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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