Protein is the main material constituting tissue cells. In addition, most hormones, enzymes, and immunoactive substances are composed of proteins, which play an important role in various life activities of the human body. Therefore, protein metabolism disorders can lead to many other syndromes such as chronic metabolic disease. Most of the human hormones are proteins, such as thyroid-stimulating hormone-releasing hormone, gonadotropin-releasing hormone, anti-diuretic hormone secreted by hypothalamus, thyroid-stimulating hormone secreted by pituitary gland, gonadotropin, growth hormone, etc., insulin and pancreas secreted by pancreatic islets Glucagon, these hormones are essentially proteins. Therefore, disorders of protein metabolism can lead to endocrine disorders, causing symptoms of endocrine disorders in the human body, symptoms such as insomnia, headache, irritability, chest tightness, tinnitus, and irregular menstruation. Disturbances in protein metabolism cause pancreatic organs to secrete insulin and glucagon abnormally, which can lead to abnormal blood glucose regulation in the human body, causing symptoms such as hypoglycemia and diabetes. Disturbances in the digestive system such as proteases, lipases, and amylases caused by protein metabolism disorders can cause dysfunction of the digestive system of the human gastrointestinal tract, cause digestive insufficiency and chronic inflammation in the gastrointestinal part. Disorders of protein metabolism can cause human brain dysfunction, leading to the generation of degenerative neuropathy and senile dementia. It can be seen that protein metabolism disorders will also lead to a variety of syndromes including endocrine system disorders, digestive system dysfunction, neurological diseases, decreased immune function, cardiovascular and cerebrovascular diseases, and genitourinary-related diseases.
Heme is an important co-group of many proteins and an important signaling molecule in many physiological processes. Heme requires an intracellular chaperone to avoid the cytotoxicity of free heme. It is formed by adding iron ions to protoporphyrin IX in the mitochondria. Researchers have found that PGRMC2 is necessary to deliver or guide unstable heme to the nucleus. Brown fat has a high demand for heme. After PGMRC2 knockout, it reduced the unstable heme in the nucleus, and enhanced the stability of the heme-reactive transcription inhibitors Rev-Erbα and BACH1. Changes in gene expression can cause severe mitochondrial defects. High-fat feeding of fat-specific PGRMC2 null mice fails to activate adaptive thermogenesis and is prone to more severe metabolic deterioration. In contrast, obese diabetic mice treated with the small molecule PGRMC2 activator showed substantial improvement in the characteristics of diabetes.
Carcinogenic metabolites include D/L-2-hydroxyglutaric acid, succinic acid, and fumaric acid. The accumulation of these metabolites in different types of cancer cells is the cause of malignant transformation. Functionally acquired mutations in isocitrate dehydrogenase result in increased levels of D-2-hydroxyglutarate, and loss of function mutations in fumarate and succinate dehydrogenase cause Accumulation of fumaric acid and succinic acid. Importantly, they are not only biomarkers of disease, but they are also capable of modification and interaction with proteins and DNA. The biological activity of many oncogenic metabolites stems from the inhibition of alpha-ketoglutarate-dependent dioxygenases, including prolyl hydroxylase, which is a key negative regulator of hypoxia-inducible factor. Carcinogenic metabolites inhibit prolyl hydroxylase, leading to an increase in HIF under normal oxygen content, which in turn induces cancer cells to change their energy metabolism from oxidative phosphorylation to glycolysis, the Warbug effect. In addition, oncogenic metabolites inhibit α-ketoglutarate-dependent TET protein and lysine demethylase, leading to high methylation of histones and DNA, explaining the association between oncogenic metabolites and epigenomes.
Other physiological activities
In addition to inhibiting enzyme activity, carcinogenic metabolites have other different physiological activities. Fumaric acid can react with sulfhydryl groups of cysteine residues. An example of this response is the KEAP1 protein, which inhibits KEAP1 activity, which in turn activates the transcription factor NRF2, driving antioxidant and anti-inflammatory gene expression. This mechanism has been shown to be responsible for the enlargement of renal cancer cysts. Fumaric acid also mediates succinylation of redox metabolic enzymes, a process that is often effectively activated in cancer cells to counteract increased reactive oxygen and nitrogen groups following metabolic remodeling. Fumaric acid is also thought to modify other metabolites, such as glutathione, thereby increasing oxidative stress and accelerating aging. Recent studies have found that D-2-hydroxyglutaric acid can inhibit the activity of branched chain amino acid transaminase and affect the synthesis of branched chain amino acids. It is worth noting that many other metabolites are also classified as carcinogenic metabolites, including glycine, glucose, and lactic acid. Most of these metabolites are related to aerobic glycolysis, glutamine breakdown, or one-carbon metabolism.