Multifunctional neuron-specific enolase: its role in lung diseases

Abstract

Neuron-specific enolase (NSE), also known as gamma (γ) enolase or enolase-2 (Eno2), is a form of glycolytic enolase isozyme and is considered a multifunctional protein. NSE is mainly expressed in the cytoplasm of neurons and neuroendocrine cells, especially in those of the amine precursor uptake and decarboxylation (APUD) lineage such as pituitary, thyroid, pancreas, intestine and lung. In addition to its well-established glycolysis function in the cytoplasm, changes in cell localization and differential expression of NSE are also associated with several pathologies such as infection, inflammation, autoimmune diseases and cancer. This article mainly discusses the role and diagnostic potential of NSE in some lung diseases.

Keywords: Chronic obstructive pulmonary disease; Enolase; Neuron-specific enolase; Pulmonary alveolar proteinosis; Solitary pulmonary nodules.

Figure 1. Enolase is a well-known glycolytic enzyme that catalyzes the interconversion of 2-phosphoglycerate and phosphoenolpyruvate during glycolysis and gluconeogenesis

Enolase, in the glycolytic pathway, is involved in the breakdown of glucose into two pyruvate molecules and the high-energy compounds ATP and cofactor NADH, providing energy and material basis for cell metabolism and various life activities. Under normoxic conditions (left panel), most of the cellular energy is obtained from oxidative phosphorylation in the mitochondria with O₂ as the terminal electron receiver in the electron transport chain to generate ∼34 ATPs/glucose molecule. However, in the absence of O₂ or under reduced oxygen conditions (hypoxia, right panel), cells resort to substrate level phosphorylation by increasing the rate of glycolysis to generate ATPs from the process. The expressions and activities of glycolytic enzymes hexokinase, enolase and pyruvate kinase are elevated to facilitate the process. Cell damaging and cancer promoting factors, including ROS, are by-products of such inefficient cellular respiratory process.

Figure 2. A simple analysis of space conformation of NSE: NSE is a metal-activated enzyme composed of two asymmetric γ subunits (brown and grey)

Two types of Mg²⁺ binding sites contribute to catalysis. Mg²⁺ binding in site I (yellow above), traditionally called ‘conformational’, induces a conformational change in the enzyme and enables binding of substrate or substrate analogues. The second Mg²⁺ ion (yellow below), called ‘catalytic’, can bind in site II and then the catalytic reaction occurs. The second Mg²⁺ ion binds in the catalytic metal ion binding site in the closed conformation loop 36–43, which includes a residue crucial for catalysis: Ser³⁹ (red). γ-enolase crystal structure (1TE6) was obtained from Protein Data Bank (PDB). The image was prepared by authors with Python.