# Opioid Peptide Synthesizing Enzymes

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $412,096

## Abstract

The prohormone convertases PC1/3 and PC2, encoded by the genes PCSK1 and PCSK2 respectively, are the 
endoproteolytic enzymes responsible for the liberation of opioid-active peptides from larger precursor 
proteins. Prohormone convertases play important roles not only in opioid peptide-mediated pain signaling 
but also function in many other neuronal circuits, including in reward pathways and in hypothalamic 
circuits involved in feeding and energy homeostasis. For example, both rare and common variations in 
PCSK1 function as major risk factors for human obesity, potentially due to deficiencies in hypothalamic 
peptidergic processing. In collaboration with clinicians who have identified children with novel mutations 
in PCSK1, we have recently determined that mutant human and mouse PC1/3 proteins are subject to 
targeting defects which are likely to result in hypothalamic proteostatic stress. Based on our prior finding 
that mouse PC1/3 proteins oligomerize during synthesis, we propose that dominant-negative interactions 
play a major role in human PC1/3 heterozygote obesity phenotypes, affecting precursor processing to 
bioactive peptides involved in satiety signaling. We propose that external stressors will exacerbate even 
mild forms of PC1/3 conformational distress, impairing C-terminal cleavage of PC1/3 to the smaller, more 
active forms. These processes will ultimately converge to strongly impair precursor processing, eg. 
proopiomelanocortin cleavage to beta-endorphin, ACTH, and most importantly, to the anorexic peptide α-
MSH. In the present proposal we will use CRISPR-engineered cell models to elucidate the cell biology and 
precursor processing efficacy of three human PC1/3 variants and mutants known to be strongly associated 
with increased risk of obesity. Secondly, we will create mouse models of two common human PCSK1 
obesity mutants, and a third model of a rare but highly impaired mutant, to extend findings made in cell 
culture to actual secretory tissues, and to identify the specific physiologic alterations which underlie the 
PCSK1-mediated obesity phenotype. Lastly, we will test our hypothesis that processing deficits in 
proopiomelanocortin-synthesizing neurons underlie the obesity phenotype by selectively eliminating Pcsk1 
expression in proopiomelanocortin-expressing cells using a floxed Pcsk1 null mouse model. The results of 
these studies will illuminate the biosynthetic mechanisms controlling hypothalamic peptide production 
that contribute to human susceptibility to a variety of diseases, from obesity to reward pathways in drug 
addiction.

## Key facts

- **NIH application ID:** 9931185
- **Project number:** 5R01DA042351-04
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** IRIS LINDBERG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $412,096
- **Award type:** 5
- **Project period:** 2017-07-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9931185

## Citation

> US National Institutes of Health, RePORTER application 9931185, Opioid Peptide Synthesizing Enzymes (5R01DA042351-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9931185. Licensed CC0.

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