Hexokinase (enzyme)

Hexokinase is an enzyme found within many forms of organic life. The primary role it plays in most organisms is acting upon the sugar glucose. Glucose contains a great deal of potential fuel that can be used by most life forms in various ways, but it needs to undergo reactions before that energy can be used. Glucose is known as a substrate, something that an enzyme acts upon.

Hexokinase and glucose are required to perform several actions that help living beings thrive. Most of these begin with glycolysis, the enzymatic breakdown of carbohydrates, such as glucose. This is a process that begins with hexokinase transforming glucose into a substance called glucose-6-phosphate. One of the most notable possibilities that glycolysis enables is the creation of a molecule called adenosine triphosphate (ATP), which stores energy in high-energy phosphate bonds. This provides one of the most effective ways for the parts of a cell to exchange energy and maintain their normal functions.

Background

German physicist and biochemist Otto Fritz Meyerhof (1884 – 1951) first used the term kinase in 1927. He was studying the functions of muscle tissue and noted that glucose and other sugars were essential in forming lactic acid. This compound is produced in muscles during anaerobic breakdown of glucose. However, he observed that glucose alone did not generate a significant amount of lactic acid. He realized that a reaction was occurring that allowed the body to process six-carbon sugars and derive lactic acid from them. He eventually discovered that enzymes were acting on the sugars, though he did not understand every step of the process.

The scientific community discovered ATP a few years later; this helped fill in the gaps of their knowledge. The name hexokinase was first known to be used in 1935. Meyerhof and other scientists continued to experiment in the late 1930s and early 1940s, learning that hexokinase could be found in far more than muscles.

One of the most important functions that hexokinase carries out is glycolysis. Initially, hexokinase interacts with glucose. As a sugar, glucose is absorbed into the body through consumption of various foods and drinks. The energy of ATP is required to complete the reaction. This molecule contributes to the reaction, resulting in adenosine diphosphate and glucose-6-phosphate. The glucose-6-phosphate undergoes more reactions that produce ATP, as well as molecules of reduced nicotinamide adenine dinucleotide, or NADH. Although glycolysis requires energy to work, the end result produces more ATP and NADH than it consumes. Both of these molecules carry substantial amounts of energy that can help power many functions within a cell.

Although very rare, some humans can lack adequate amounts of hexokinase. This genetic disorder is referred to as hexokinase deficiency. It has been associated with mutations in the gene that produces hexokinase, usually involving the HK1 gene. It is possible for people to be carriers of the genes and possibly pass on the deficiency to children while not having the disorder themselves. The gene is recessive, so only someone who inherited it from both parents would have the deficiency.

In the most severe cases, this disorder can lead to nonspherocytic hemolytic anemia. Without enough hexokinase, red blood cells in the body do not get enough energy, which leads to the cells dying off at a rate faster than they can be replaced, and the blood does not perform its proper function. This can cause the person to feel weak and exhausted. More severe cases can also lead to diabetes and gallbladder infections. The most effective treatment in these cases consists of blood transfusions, allowing healthy red blood cells to supplement the weakened ones.

Overview

Hexokinase is found in a wide variety of life forms, including bacteria, fungi, plants, and many vertebrate animals. Despite many structural differences between the types found in different beings, the known variants tend to share a close association with ATP. They are named for their capacity to react with particular sugar molecules made up of six carbon atoms. Glucose is the most commonly known, but various types of hexokinase can act on a wide variety of sugars.

Four distinct types of hexokinase are found in mammals. Hexokinase I, or A, is the most common, and is found in most types of tissue. Its general function is to help provide energy for long-term, basic bodily functions. It does not react to moment-to-moment situations, such as increases of adrenaline or hormonal shifts. Hexokinase II, or B, is primarily concentrated in the heart and muscles. Researchers have discovered relatively little about the unique traits of hexokinase III, or C. These three forms of hexokinase are significantly inhibited by glucose-6-phosphate. This means they are less active and capable of causing reactions when a concentration of glucose-6-phosphate is present. Hexokinase IV is also known as hexokinase D, or glucokinase. It is most prominent in the liver, pancreas, hypothalamus, and small intestine. Its affinity to glucose is much lower than that of hexokinase I, II, and III. Its actions are coded by genes entirely different from its counterparts, which allows it to function at a different rate than the others. It is also much less prone to inhibition by glucose-6-phosphate than types I, II, and III. In 2022, researchers reported that hexokinase I can affect glucose processing or immune response depending on whether it is bound to mitochondria or located in the cytoplasm.

The first three types of hexokinase are primarily designed to meet demand. If the body is lacking glucose-6-phosphate, they help produce it. If the body has an ample supply, internal inhibitions will stop them from producing more. This prevents the body from becoming overwhelmed with an unnecessary substance, and allows it to store glucose to be used when the energy from it is required. However, the organs in which glucokinase operates have different requirements. They need a supply-based structure, converting glucose to glucose-6-phosphate as it enters, regardless of the amount. Glucokinase’s lack of inhibition allows it to do this. Studies used NMR spectroscopy to report that the protein myeloid cell leukemia 1 (MCL1) binds with and increases the enzymatic activity of hexokinase II to increase glucose metabolism, leading to and worsening cancer.

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