Role Of Metabolic Enzymes-All About Cell Metabolism

For decades, one of the biggest challenges in biology is to ameliorate a clear and complete understanding of the numerous mechanisms that emphasize the deficiency of metabolic enzymes and how they can have an impact on human health. However, it has now been manifested that metabolic enzyme deficiency (MED) could either be acquired (carrying a high risk of interrupted biochemical reactions) or inherited as an inborn error of metabolism (IEM).

The deficiency of metabolic enzymes can lead to the accumulation of toxic compounds that may result in the failure of the production of vital biological compounds or disruption of normal organ functions. Health disorders associated with a deficiency of metabolic enzymes can involve almost any organ system of the human body.

Role Of Metabolic Enzymes

Metabolic Enzymes are known to perform a wide range of cellular functions that are required for homeostasis and survival, including energy storage, cellular respiration, digestion, proteolysis, transcription, and response to the environment. In other words, these life-sustaining pathways are critical when it comes to the growth and maintenance of cellular integrity. They encompass numerous protein classes, including but not limited to lipoxygenases, oxidoreductases, carboxylases, dehydrogenases, transferases, kinases, and lyases.

It is worthwhile to note that a certain set of metabolic pathways helps organisms maintain structures and compartments, grow and reproduce, and respond to environments. Metabolic pathways generally cover a comprehensive range of enzyme activities from the "classic" catabolic and  anabolic reactions of metabolites, to the "novel" regulatory roles in organelle biogenesis and signaling pathways.

A clear and complete understanding of this delicate metabolic network can likely provide novel therapeutic intervention in inherited metabolic disorders, oncology, degenerative diseases, and inflammation. Deregulation of metabolic pathways can be associated with severe and debilitating conditions such as cancer, hormonal disorders, osteoporosis, diabetes, hypertension, and obesity.

Enzymes are beneficial when it comes to breaking down of large nutrient molecules such as fats, carbohydrates, and proteins, into smaller molecules. This process gets initiated during the stage of digestion in the intestines and stomach of animals. Conversely, some enzymes are entrusted with the task of guiding broken-down, smaller molecules through the body's intestinal walls into the bloodstream. In addition to this, enzymes perform a wide range of other functions that include storing and releasing energy, the processes of respiration, the course of reproduction, and vision. For instance, the enzyme thrombin promotes the healing of wounds and the enzyme lysozyme kills bacteria. If this is not all, enzymes can also be used to regulate enzyme abnormalities and deficiencies resulting from diseases. In other words, enzymes are indispensable to life.

Metabolic Enzymes Deficiency: Cause and Complications

Glucose-6-phosphatase (G6Pase) Deficiency

G6Pase is instrumental in the formation of Glucose-6-phosphatase from glucose in the endoplasmic reticulum's lumen. It is worth noting here that the activity of G6Pase is restricted to the different gluconeogenic tissues such as kidney, liver, β-cells of the endocrine pancreas, and the small intestine. The deficiency of G6Pase activity in kidney, liver, and intestinal mucosa with excessive glycogen accumulation in these organs may result in glycogen storage disease (GSD) type 1 (Von Gierke’s disease), which is characterized by hypoglycemia.

Fructose-1,6-bisphosphatase (FBPase) Deficiency

FBPase can be described as a unique enzyme in the gluconeogenetic pathway that gets regulated through the alteration of the inactive (T) and active (R) conformational isomeric states that catalyzes the magnesium dependent reversible production of fructose-1,6-bisphosphate from inorganic phosphate and fructose-6-phosphate.

FBPase deficiency, the liver's metabolic recessive disorder, is characterized by the life-threatening episodes of hypoglycemia, apnoea, lactic acidosis, hyperventilation, and ketosis.

Phosphoenolpyruvate Carboxykinase (PEPCK) Deficiency

An essential marker for gluconeogenesis, PEPCK catalyzes the conversion of phosphoenolpyruvate to oxaloacetate. PEPCK1 (cytosolic) and PEPCK2 (mitochondrial) are the different isoforms of PEPCK. PEPCK1 is regulated in the human body by the mitochondrial guanosine triphosphate (GTP)-dependent pathways, including substrate supply, hormones, and purine nucleotides. PEPCK2 is principally involved in gluconeogenesis.

The specific symptoms of PEPCK deficiency are linked with hepatomegaly, glucagon insensitivity, developmental delay, hypotonia, lactic acidosis, hypoglycemia, and massive fat deposition in liver and kidneys.

Pyruvate Dehydrogenase Complex (PDHC) Deficiency

Pyruvate Dehydrogenase Complex is highly involved in the conversion of pyruvate to acetyl-coenzyme A. The complex includes three different enzymes: pyruvate decarboxylase (E1), dihydrolipoyl transacetylase (E2), and dihydrolipoyl dehydrogenase (E3). The deficiency of PDHC is believed to be one of the most common genetic and neurodegenerative disorders that are usually linked to abnormal mitochondrial metabolism.

It is worth noting that the clinical spectrum of PDHC deficiency can be divided into neurological as well as metabolic manifestations. Neurological presentations include dysplasia of the dentate nuclei, pachygyria, mental retardation, hypotonia, spasticity, and Leigh syndrome. On the other hand, PDHC's metabolic manifestation happens at neonatal period due to lactic acidosis.

All in all, the study of cellular metabolism, especially metabolic enzymes, has been rigorously revisited over the last few years. Among these insights is the discovery that numerous metabolic enzymes are capable of surprising activities outside of their established metabolic roles, including in the regulation of DNA damage repair, cell cycle progression, gene expression, and apoptosis. A big majority of these newly-identified functions are activated in response to nutrient and oxygen availability, growth factor signaling, and external stress.

In the recent past, an increasing number of studies have been able to highlight the unexpected and significant features of metabolic enzymes that have already changed or can possibly change the classic concepts found in the biochemistry textbooks.