Influe"N"za- and you

If you were a victim of the 2009 H1N1 outbreak, you are familiar with influenza's right-hand protein, neuraminidase. While you were coughing, wheezing, aching and exhausted, neuraminidase was throwing a rave in your respiratory tract. This essential protein maintains the life cycle of the influenza virus by allowing newly made viruses to leave the cell, as shown below:

source: http://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summary_pr?p_JournalId=2&p_RefId=923098&p_IsPs=N

Specifically, neuraminidase is a structural glycoprotein that cleaves the interaction between hemagluttinin (the "H" in H1N1) and sialic acid. It facilitates the removal of the viral particles by removing the N-acetyl nueraminic acid receptor, shown in the following reaction:

source: http://www.oup.com/uk/orc/bin/9780199234479/01student/mcqs/ch20/

Neuraminidase exists of a tetramer of the following subunit, shown here in two different views:

The sialidase activity of neuraminidase has been found to be active even under very acidic conditions (pH 4.0), which may have contributed to the severe virulence of the 1918 "Spanish Flu" pandemic. Because the influenza virus can mutate efficiently and effectively, the chances are increasing that a more dangerous form of the virus will soon emerge. Neuraminidase inhibitors (anti-flu drugs) such as Oseltamivir and Zanamivir are becoming more available for use against this protein, but until we can find an effective way to stop it, we will forever live in fear of the next influenza pandemic. 

Neuraminidase is a fascinating glycoprotein, but its dangerous enzymatic activity has forced it to become a terrifying monster lurking in the shadows. So the next time you are lying in bed for days feeling horribly, you can ponder the power of neuraminidase and knowledgeably inform your caretakers of its activity within your body. I'm sure that they will be most grateful!!

References:

Takahashi, T., Y. Kurebayashi, K. Ikeya, et al. The low pH stability discovered in neuraminidase of 1918 pandemic influenza A virus enhances viral replication. PLoS One 5(12): e15556.

Tisoncik, Jennifer, Ying Guo, Katie Cordero, et al. Identification of critical residues of influenza neuraminidase in viral particle release. Virology Journal 8(14).

Zhang, C., Y.L. Cao, W. Zhong, et al. Establishment of a cell-based 2009 H1N1 influenza neuraminidase inhibitors evaluation system. Yao Xue Xue Bao. 45(3): 383-387.

Assignment 2

In this post, we will explore a little bit of the literature about neuraminidase. I learned some fascinating facts about the structure and function of the protein and I hope you will enjoy them as well. Neuraminidase is a dangerous little protein- without it, influenza epidemics would be mere historical horror stories instead of current threats. It is a prime target for anti-influenza drugs.

Zhang, C., Y.L. Cao, W. Zhong, et al. Establishment of a cell-based 2009 H1N1 influenza neuraminidase inhibitors evaluation system. Yao Xue Xue Bao. 45(3): 383-387.

                In this article, the researchers were evaluating compounds that might inhibit neuraminidase function. They described neuraminidase as an influenza virus structural protein that cleaves the interaction between hemagglutinin and sialic acid, allowing the viral particles to be released from the cell. Hemagluttinin is the other structural protein in the influenza virus- the “H” in H1N1. Neuraminidase is, if you can believe it, the “N” in H1N1. Hemagluttinin aids in attaching the virus to the host cell. In this article, several compounds that were candidates for anti-influenza drugs were being researched for their potential to inhibit the activity of neuraminidase, preventing viral release from the host cell. This would be able to stop the virus from spreading to other cells.

Tisoncik, Jennifer, Ying Guo, Katie Cordero, et al. Identification of critical residues of influenza neuraminidase in viral particle release. Virology Journal 8(14).

                This article states that neuraminidase catalyzes the N-acetyl neuraminic acid (Neu5Ac) receptor removal, which makes the release of the viral particles from the host cell easier. Neuraminidase is essential to viral survival within the host. The researchers found several residues on the protein that were facing away from the structure of the virus, which may signal their importance to the function of the protein. It mentions that neuraminidase exists as a tetramer (meaning that it has four subunits), composed of the same subunit (shown in pictures in previous post). This subunit is the same across all types of influenza.

Takahashi, T., Y. Kurebayashi, K. Ikeya, et al. The low pH stability discovered in neuraminidase of 1918 pandemic influenza A virus enhances viral replication. PLoS One 5(12): e15556.

                The researchers of this article were hypothesizing about how the 1918 “Spanish flu” influenza A pandemic was so virulent. They found that the neuraminidase protein in this strain was stable in lower pH levels than normal strains. In this experiment, the sialidase activity of neuraminidase was unhindered by acidic conditions of pH 4.0, which most other strains do not tolerate.  They deleted a threonine residue at position 435 and a glycine residue at position 455 eliminated this ability to remain stable in acidic conditions. The researchers concluded that this is why the 1918 pandemic influenza virus was able to replicate so efficiently within its host.

Do you see what I mean? Neuraminidase is scary, but really cool! And because it can mutate so quickly (why there are different types of influenzas), it can adapt to all sorts of new environments... such as your body. Yikes!

Assignment 1

Here are several different views of the protein. 

This first view is called a "cartoon" view, which shows the secondary structures. There are a lot of beta sheets, apparently, in nueraminadase.

This next view is a ribbon diagram of the main chain- the only chain, in this case!

The next view shows each one of the elements as spheres. The protein has horns!

This is called the "mesh" view. Stretchy looking!

This view is colored by element. There are a lot of carbons (green) and some hydrogens (blue).

Awesome; hope you had fun exploring different views of neuraminadase with me!