Molecular mechanisms of the effect of standardized placental hydrolysate peptides on mitochondria functioning

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Abstract

Background. Human placenta hydrolysates (HPH), the study of which was initiated by the scientific school of Vladimir P. Filatov, are currently being investigated using modern proteomic technologies. HPH is a promising tool for maintaining the function of mitochondria and regenerating tissues and organs with a high content of mitochondria (liver, heart muscle, skeletal muscles, etc.). The molecular mechanisms of action of HPH are practically not studied.

Aim. Identification of mitochondrial support mitochondrial function-supporting peptides in HPH (Laennec, produced by Japan Bioproducts).

Materials and methods. Data on the chemical structure of the peptides were collected through a mass spectrometric experiment. Then, to establish the amino acid sequences of the peptides, de novo peptide sequencing algorithms based on the mathematical theory of topological and metric analysis of chemographs were applied. Bioinformatic analysis of the peptide composition of HPH was carried out using the integral protein annotation method.

Results. The biological functions of 41 peptides in the composition of HPH have been identified and described. Among the target proteins, the activity of which is regulated by the identified peptides and significantly affects the function of mitochondria, are caspases (CASP1, CASP3, CASP4) and other proteins regulating apoptosis (BCL2, CANPL1, PPARA), MAP kinases (MAPK1, MAPK3, MAPK4, MAPK8, MAPK9 , MAPK10, MAPK14), AKT1/GSK3B/MTOR cascade kinases, and a number of other target proteins (ADGRG6 receptor, inhibitor of NF-êB kinase IKKE, pyruvate dehydrogenase 2/3/4, SIRT1 sirtuin deacetylase, ULK1 kinase).

Conclusion. HPH peptides have been identified that promote inhibition of mitochondrial pore formation, apoptosis, and excessive mitochondrial autophagy under conditions of oxidative/toxic stress, chronic inflammation, and/or hyperinsulinemia.

About the authors

Ivan Yu. Torshin

Computer Science and Control

Email: unesco.gromova@gmail.com
ORCID iD: 0000-0002-2659-7998

канд. физ.-мат. наук, канд. хим. наук, вед. науч. сотр. ФИЦ ИУ РАН

Russian Federation, Moscow

Olga A. Gromova

Computer Science and Control

Author for correspondence.
Email: unesco.gromova@gmail.com
ORCID iD: 0000-0002-7663-710X
Scopus Author ID: 7003589812

д-р мед. наук, проф., вед. науч. сотр. ФИЦ ИУ РАН

Russian Federation, Moscow

Olga V. Tikhonova

Orekhovich Research Institute of Biomedical Chemistry

Email: unesco.gromova@gmail.com
ORCID iD: 0000-0002-2810-566X

канд. биол. наук, рук. Центра коллективного пользования «Протеом человека» ФГБНУ «НИИБМХ им. В.Н. Ореховича»

Russian Federation, Moscow

Alexander G. Chuchalin

Pirogov Russian National Research Medical University

Email: unesco.gromova@gmail.com
ORCID iD: 0000-0002-6808-5528

акад. РАН, д-р мед. наук, проф., зав. каф. госпитальной терапии педиатрического фак-та, председатель правления Российского респираторного общества

Russian Federation, Moscow

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Supplementary files

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2. Fig. 1. Structures of caspases and calpain. The binding surfaces in the active site of kinases with which Laennec peptides interact are shown: a – spatial structure of caspases (e.g., CASP1, PDB file 1bmq); b – spatial structure of μ-calpain, PDB file 4ZCM.

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3. Fig. 2. MAPK spatial structure. The ligand binding surface in the active kinase site with which Laennec peptides can interact is shown: a – by the example of MAPK3 (ERK1) and MAPK1 (ERK2), PDB file 2ZOQ; b – MAPK8 (JNK1, PDB file 2XS0); c – MAPK9 (JNK2, PDB file 3NPC).

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4. Fig. 3. Protein kinase B (PKB) and its substrates: a – spatial structure of PKB (PDB file 5KCV); b – substrate patterns of the amino acid sequence phosphorylated by PKB.

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5. Fig. 4. SIRT1 and ULK1 kinase: a – spatial structure of SIRT1 (PDB file 4ZZH); b – spatial structure of ULK1 kinases (PDB file 4WNO).

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