Human endogenous metabolic compounds are some of the metabolites produced and found in the human body. The role of these metabolites cannot be underestimated. And this article will mainly introduce its application in disease diagnosis and drug discovery.
1 Endogenous metabolites can be used for disease diagnosis
Diseases lead to changes in the body's pathophysiological processes, and ultimately lead to corresponding changes in metabolites. Metabolomics is a newly developed discipline following genomics and proteomics. It searches for disease biomarkers through qualitative and quantitative analysis of small molecular metabolites with a relative molecular weight of less than 1,000 in a certain organism or cell. Metabolomics provides a better method of disease diagnosis. In the field of cancer research, methods for diagnosing malignant tumors, screening drugs, and evaluating drug toxicity by observing the abnormal changes of related small molecule metabolism markers inside and outside tumor cells have gradually become research hotspots. Cancer cells have a unique metabolic phenotype that is different from normal cells. Monitoring the fluctuations of small molecular metabolites in the metabolism of cancer cells will help predict the progression of tumors, understand the metabolic pathways of substances in the body, explore the pathogenesis of cancer and the mechanism of action of drugs.
Current researchers are mainly focused on the research of compounds related to energy metabolism of cancer cells, such as nucleosides, amino acids, lipids, and carbohydrates. A variety of tumor-related lipid markers have been found, such as choline, phosphocholine, phospholecithin, cholesterol, etc. Pyruvate, lactic acid, isobutyric acid, etc. are biomarkers related to carbohydrate metabolism of tumor cells. Exploring strategies to treat malignant tumors by targeting lipid metabolism and sugar metabolism pathways is attracting attention.
2 Endogenous metabolites can be used for drug discovery
In addition to being used as disease markers, human endogenous compounds also play a very important physiological role. A large number of research results have confirmed that many diseases are closely related to the abnormal changes of endogenous substances. Therefore, it has become one of the ways of new drug research to find drugs to treat diseases by studying endogenous active substances. In addition, studying the process of biological activity in the body, biologically active substances, and metabolites of biological transformation in the body are also one of the main ways for the discovery of lead compounds. So far, about 500 drug targets have been discovered, of which receptors, especially G-protein coupled receptors (GPCR) targets, account for the vast majority. Drug molecules can be designed based on the chemical structure characteristics of potential drug targets, such as enzymes, receptors, ion channels, nucleic acids, etc., as well as their endogenous ligands and natural substrates revealed in life science research. At present, a large number of studies have confirmed the biological activity of some human endogenous metabolites. Here are some examples:
(1)Sulfur-containing amino acid metabolites and cardiovascular damage/repair
There is an endogenous sulfur-containing amino acid metabolic pathway starting from methionine in mammals. In this pathway, homocysteine (Hcy), cystathionine and cysteine are important intermediate metabolites, while taurine, hydrogen sulfide (H2S) and sulfur dioxide (SO2) are the end products of metabolism. These active molecules from the same metabolic source have relatively independent biological effects, but they interact with each other to form a group of sulfur-containing amino acid metabolism molecules with a network regulation relationship. They are important substances for the regulation of biological homeostasis, and play an important regulatory role in the process of cardiovascular damage and repair. Homocysteine (Hcy) is a multifunctional damage factor that can damage cell structure and function. Endogenous H2S is an important cardiovascular defense system of the body, which can regulate the cardiovascular system extensively. Taurine has the effects of antagonizing atherosclerosis, hypertension and insulin resistance, and is a broad-spectrum protective agent of cardiovascular cell.
(2)Abnormal kynurenine metabolic pathway and central nervous system disease repair
The kynurenine pathway (KP) is an important pathway for tryptophan metabolism in the brain. In recent years, studies have found that the physical and chemical changes of a variety of central nervous system diseases are related to the metabolic disorders of this pathway. The main function of KP is to promote glycolysis, inhibit gluconeogenesis, provide necessary material and energy support for brain tissue, and is particularly important for neuron protection under inflammatory stimulation and cytotoxicity. In addition, some of the derivatives in KP can affect the content and function of neurotransmitters in the brain, and are of great significance to the occurrence and regulation of central nervous system diseases.
(3)Human endogenous small molecules promote tumor stem cell differentiation and prevent tumor proliferation
Researchers have discovered that ITE, a metabolite of tryptophan, can promote the differentiation of cancer stem cells. In brain gliomas and liver cancer cells, the endogenous tryptophan metabolite ITE [2-(1'H3'-indolecarbonyl)thiazole-4-carboxylic acid methyl ester) can act as a ligand to activate the nuclear transcription factor of aromatic hydrocarbon receptors, and promotes the binding of AhR in the promoter region of the core stem factor Oct4 gene and inhibits the transcription of Oct4. When amino acid depletion or local hypoxia in the tumor leads to a decrease in the concentration of ITE, the originally bound AhR will break away from the Oct4 promoter, which will increase the expression of Oct4 and initiate the formation of cancer stem cells. After adding chemically synthesized exogenous ITE, the up-regulation of Oct4 expression was effectively inhibited and reversed, and tumor stem cells differentiated. After ectopic or in situ inoculation of tumor cells into nude mice to form transplanted tumors, intraperitoneal injection or intratumor injection of ITE can significantly inhibit tumor proliferation.
It can be seen that human endogenous metabolites play an extremely important physiological role, and in recent years, some researchers have proposed that the "metabolite-likeness" of drugs can be used as one of the evaluation indicators for screening drug. Some studies have evaluated the similarity between marketed drugs and drug screening compound libraries and endogenous metabolites, and found that marketed drugs and endogenous metabolites are more similar. According to analysis, the reasons may be twofold: On the one hand, most drugs need the assistance of solute carriers to enter cells. These solute carriers are used to transport endogenous metabolites in the body, and drugs similar to endogenous metabolites are more likely to bind to these solute carriers and enter cells. On the other hand, drugs may bind to their targets in a similar way to natural substrates, so drugs and endogenous metabolites have a higher similarity.