A peptidomics screening of milk hydrolysate identified two peptides (AYFYPELFR and HLPLPLLQSW) that inhibit ACE, the enzyme targeted by common blood pressure medications.
31 of 478 peptidesOut of 478 peptides identified in milk hydrolysate, 31 were confirmed as ACE substrates, with two showing significant inhibitory activity against angiotensin I hydrolysis
What the researchers found
Using an integrated peptidomics screening approach, researchers identified 31 ACE substrates from 478 peptides found in milk hydrolysate. The study revealed specific rules governing which peptides ACE can cleave: the most common residue at the P1' cleavage position was leucine or serine, while ACE would not cleave peptides when P1' is proline, P2' is aspartate/glutamate, or P1 is isoleucine.
Two peptides — AYFYPELFR and HLPLPLLQSW — were identified as substrate-type ACE inhibitors that significantly slowed the breakdown of angiotensin I, the natural ACE substrate involved in blood pressure regulation. These milk-derived peptides could serve as natural ACE inhibitors.
Why it matters
ACE (angiotensin-converting enzyme) is the target of widely prescribed blood pressure drugs like lisinopril and enalapril. Identifying natural peptide inhibitors of ACE from food sources like milk could lead to functional foods or nutraceuticals with blood pressure-lowering properties. This study's peptidomics screening method also provides a systematic way to discover bioactive peptides from any food protein hydrolysate, accelerating the discovery of health-promoting peptides.
The numbers in context
478 peptides identified · 31 ACE substrates confirmed · 2 substrate-type inhibitors: AYFYPELFR and HLPLPLLQSW · P1' preference: Leu/Ser · ACE blocked by Pro at P1', Asp/Glu at P2', Ile at P1
How the study worked
The researchers integrated three techniques: ACE pre-incubation with milk hydrolysate peptides, liquid chromatography-mass spectrometry (LC-MS), and stable-isotope labeling. This allowed them to systematically identify which peptides in the complex mixture are ACE substrates. Activities were confirmed using synthetic peptides. The protective effects of identified substrates against ACE-mediated hydrolysis of angiotensin I were also tested.
Who was studied
Not applicable (in vitro peptidomics study using milk hydrolysate)
What this study cannot tell us
This is an in vitro biochemical study — the identified peptides have not been tested in living organisms. Whether these milk-derived peptides survive digestion, are absorbed intact, and reach ACE in the body at effective concentrations remains unknown. The two inhibitory peptides are relatively large (9–10 amino acids), which may limit their oral bioavailability.
How to read the evidence
This is a preliminary in vitro biochemistry study. While the peptidomics screening method is rigorous and the substrate identifications were confirmed with synthetic peptides, no animal or human data are presented. The evidence is preliminary for health claims but solid for biochemical characterization.
When this study was published
Published in 2023, this study reflects the current state of peptidomics approaches to discovering bioactive food-derived peptides.
The bigger picture
Food-derived bioactive peptides are a rapidly growing area of research, with ACE-inhibitory peptides being among the most studied. Some milk-derived peptide products have already been commercialized in Japan and Europe as functional foods for blood pressure management. This study advances the field by providing a systematic screening platform and uncovering specific structural rules for ACE-peptide interactions. The substrate-type inhibition mechanism — where the peptides compete with angiotensin I for ACE's active site — is particularly relevant for understanding how food peptides might exert blood pressure effects.
Questions still open
- Do AYFYPELFR and HLPLPLLQSW survive gastrointestinal digestion and reach the bloodstream in active form after oral consumption?
- Could this peptidomics screening approach be applied to other food protein sources to discover novel ACE-inhibitory peptides?
- Would daily consumption of milk hydrolysate enriched in these peptides produce clinically meaningful blood pressure reductions?
Common questions
What is ACE and why do people take drugs to inhibit it?
Can drinking milk lower blood pressure through these peptides?
Read the original research
An Efficient Peptidomics Screening for Exogenous Substrates and Inhibitory Peptides of the Dipeptidase ACE from Milk Hydrolysate.
Pharmaceutics, 15(2)
Citation
Huang, Ju-Hsuan; Nong, Nhung Thi Phuong; Hsu, Jue-Liang. (2023). An Efficient Peptidomics Screening for Exogenous Substrates and Inhibitory Peptides of the Dipeptidase ACE from Milk Hydrolysate.. Pharmaceutics, 15(2). https://doi.org/10.3390/pharmaceutics15020425