Biliverdin reductase is an enzyme—a type of protein that speeds up chemical reactions—present in the cells of mammals and many other vertebrates. This protein is found in virtually all tissues, though it is especially concentrated in the liver and spleen. Its fundamental job is to chemically change one specific molecule into another. The enzyme operates within different cellular compartments and can adjust its function based on the chemical environment.
The Role in Heme Breakdown
Every day, millions of red blood cells reach the end of their 120-day lifespan and are removed from circulation. When these cells are broken down, the body must manage a component called heme, which is part of the hemoglobin protein that carries oxygen. Heme must be catabolized, or broken down, because its accumulation would be toxic. This process occurs in two main steps, carried out by macrophages in the spleen, liver, and bone marrow.
The first step in heme degradation is managed by an enzyme named heme oxygenase. This enzyme chemically cleaves the heme molecule, which releases iron to be recycled and a small amount of carbon monoxide. The remaining structure is converted into a green-pigmented molecule called biliverdin. It is at this stage that biliverdin reductase performs its most well-known function.
Biliverdin reductase then catalyzes the second and final step of this pathway. It facilitates a reaction that adds hydrogen to biliverdin, a process known as reduction. This reaction converts the green pigment into a yellow-orange pigment known as bilirubin. A familiar example of this process is the changing color of a bruise, where the initial purplish color fades to green as heme is converted to biliverdin, and then to yellow as biliverdin is converted into bilirubin.
The Significance of Bilirubin
For many years, bilirubin was regarded simply as a metabolic waste product. Because high concentrations can be harmful, the body has a system to dispose of it. In the liver, bilirubin is attached to glucuronic acid, which makes it water-soluble and allows it to be excreted in bile and urine. This disposal process is what gives these waste products their characteristic colors.
This perspective has evolved, as research has revealed that bilirubin possesses a beneficial biochemical property. It is now understood to be a powerful native antioxidant. Antioxidants are molecules that protect cells from damage caused by unstable molecules called reactive oxygen species, which are natural byproducts of metabolism. This cellular damage, often called oxidative stress, is implicated in a wide range of health issues.
The protective effect of bilirubin is enhanced by the biliverdin-bilirubin redox cycle. When bilirubin neutralizes a harmful reactive oxygen species, it becomes oxidized and reverts to its precursor, biliverdin. Biliverdin reductase then promptly reduces this biliverdin back into bilirubin, regenerating the antioxidant. This efficient recycling allows a small amount of bilirubin to provide a continuous defense against cellular damage.
Beyond Heme: Broader Cellular Functions
Biliverdin reductase is a multifunctional protein with roles extending beyond its activity in heme breakdown. It participates in the complex communication networks within cells, known as cell signaling pathways. This means it can influence major cellular processes, including growth, metabolism, and responses to external stimuli.
Under certain conditions, such as cellular stress, biliverdin reductase can relocate from its usual position in the cell’s cytoplasm into the nucleus. Once inside the nucleus, it can function as a transcription factor, a type of protein that binds to DNA and regulates the activity of specific genes. For example, it can influence genes involved in the body’s stress response.
This protein also has a notable interaction with the insulin signaling pathway, which is fundamental to how the body regulates blood sugar. Biliverdin reductase can act as a scaffold, bringing other signaling proteins together, and can modulate the signals sent when insulin binds to a cell’s surface. By influencing these pathways, it plays a part in controlling glucose metabolism.
Connection to Health and Disease
The functions of biliverdin reductase and its product, bilirubin, have direct connections to human health and disease. Issues can arise when the heme breakdown pathway is dysregulated. A common example is neonatal jaundice, where newborns develop a yellowish tint to their skin and eyes. This occurs because the infant’s liver is not yet mature enough to efficiently process the bilirubin produced from the normal breakdown of red blood cells.
Conversely, the antioxidant capacity of the biliverdin-bilirubin system is associated with protective effects against conditions driven by oxidative stress. Research suggests that mildly elevated levels of bilirubin are correlated with a lower incidence of cardiovascular diseases. This is partly because bilirubin helps prevent the oxidation of low-density lipoproteins (LDL), a step in the formation of atherosclerotic plaques in arteries.
This protective role also extends to the nervous system. Oxidative stress is a contributing factor in the progression of several neurodegenerative disorders, and the brain is particularly vulnerable to this type of damage. The antioxidant activity of bilirubin, maintained by biliverdin reductase, provides a defense mechanism that helps preserve neuron function.