A Quantitative Systems Pharmacology Model of Human Leucine Metabolism
- 1Pfizer Inc Cambridge Massachusetts USA
- 2JuliaHub Cambridge Massachusetts USA
- 3Department of Mathematics CSAIL Cambridge Massachusetts USA
Abstract
Branched‐chain amino acids (BCAAs) are essential dietary components that humans cannot synthesize. Altered BCAA levels have been associated with biomarkers or potential risk factors in several metabolic disorders, including insulin resistance, type 2 diabetes, obesity, and cardiovascular disease. However, the underlying mechanisms regulating BCAA metabolism and how cellular or signaling modifications may alter BCAA levels are yet to be fully elucidated. To investigate the fate of plasma and intracellular leucine, we developed a mathematical model of human leucine metabolism. Through a virtual population approach, the model was constructed based on known biology and data and calibrated to fit available acute leucine and α‐ketoisocaproic acid (KIC) clinical challenge data in healthy subjects. The rate‐limiting step of BCAA catabolism is oxidative decarboxylation by branched‐chain α‐ketoacid dehydrogenase (BCKDH), a process that is negatively regulated by phosphorylation by branched‐chain α‐ketoacid dehydrogenase kinase (BDK). Recent preclinical studies have reported that inhibition of BDK leads to significant lowering of plasma BCAA levels. Modeling predicts that the magnitude of reduction observed in plasma BCAA and BCKA levels upon BDK inhibition may require incorporation of an additional regulatory mechanism, such as feedback on leucine and KIC uptake into tissues. This leucine systems model has implications for drug discovery and development, enables a mechanistic understanding of clinical data, and could be used as a tool for the design and analysis of therapeutic modifications of leucine and KIC metabolism.
Related
- Targeted Quantitative Analysis of Polar and Phosphorylated Intermediates of Algal and Plant Primary Carbon Metabolism Using an Optimized HILIC-Amide Tandem MS Workflow
- Leucine‐rich glioma inactivated 1 ( LGI1 ) is a ganglioside‐binding protein
- The AMPK signaling pathway in cell metabolism and human diseases
- A Minimally Perturbative DARPin Probe for Quantitative Fluorescence Imaging of the Human TCR-CD3 Complex
- Burdock (Arctium lappa L.) Root Extract Induces Transcriptional Signatures Associated with Metal Homeostasis and Lipid Metabolism in Human Keratinocytes.
BibTeX
@article{herron2026quantitative,
title = {{A Quantitative Systems Pharmacology Model of Human Leucine Metabolism}},
author = {J. Cody Herron and Anna Sher and Yingbo Ma and Elisabeth Roesch and Sebastian Miculța‐Câmpeanu and Christopher Rackauckas and Kevin J. Filipski and Rachel Roth Flach and Theodore R. Rieger and Cynthia J. Musante and Richard Allen},
journal = {CPT: Pharmacometrics \& Systems Pharmacology},
year = {2026},
month = sep,
doi = {10.1002/psp4.70328},
url = {https://doi.org/10.1002/psp4.70328},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - A Quantitative Systems Pharmacology Model of Human Leucine Metabolism
AU - J. Cody Herron
AU - Anna Sher
AU - Yingbo Ma
AU - Elisabeth Roesch
AU - Sebastian Miculța‐Câmpeanu
AU - Christopher Rackauckas
AU - Kevin J. Filipski
AU - Rachel Roth Flach
AU - Theodore R. Rieger
AU - Cynthia J. Musante
AU - Richard Allen
PY - 2026
DA - 2026/09/17
JO - CPT: Pharmacometrics & Systems Pharmacology
DO - 10.1002/psp4.70328
UR - https://doi.org/10.1002/psp4.70328
AB - Branched‐chain amino acids (BCAAs) are essential dietary components that humans cannot synthesize. Altered BCAA levels have been associated with biomarkers or potential risk factors in several metabolic disorders, including insulin resistance, type 2 diabetes, obesity, and cardiovascular disease. However, the underlying mechanisms regulating BCAA metabolism and how cellular or signaling modifications may alter BCAA levels are yet to be fully elucidated. To investigate the fate of plasma and intracellular leucine, we developed a mathematical model of human leucine metabolism. Through a virtual population approach, the model was constructed based on known biology and data and calibrated to fit available acute leucine and α‐ketoisocaproic acid (KIC) clinical challenge data in healthy subjects. The rate‐limiting step of BCAA catabolism is oxidative decarboxylation by branched‐chain α‐ketoacid dehydrogenase (BCKDH), a process that is negatively regulated by phosphorylation by branched‐chain α‐ketoacid dehydrogenase kinase (BDK). Recent preclinical studies have reported that inhibition of BDK leads to significant lowering of plasma BCAA levels. Modeling predicts that the magnitude of reduction observed in plasma BCAA and BCKA levels upon BDK inhibition may require incorporation of an additional regulatory mechanism, such as feedback on leucine and KIC uptake into tissues. This leucine systems model has implications for drug discovery and development, enables a mechanistic understanding of clinical data, and could be used as a tool for the design and analysis of therapeutic modifications of leucine and KIC metabolism.
SN - 2163-8306
ER -