Blood breakdown product commandeers important enzyme

Date:
September 4, 2020
Source:
University of Bonn
Summary:
The hemoglobin in the red blood cells ensures that our body cells
receive sufficient oxygen. When the blood pigment is broken down,
'heme' is produced, which in turn can influence the protein cocktail
in the blood.

Researchers have now discovered in complex detective work that the
'activated protein C' (APC) can be commandeered by heme. At the
same time, APC can also reduce the toxic effect of heme.



FULL STORY ==========================================================================
The hemoglobin in the red blood cells ensures that our body cells
receive sufficient oxygen. When the blood pigment is broken down,
"heme" is produced, which in turn can influence the protein cocktail in
the blood. Researchers at the University of Bonn have now discovered
in complex detective work that the "activated protein C" (APC) can be commandeered by heme. At the same time, APC can also reduce the toxic
effect of heme. Perspectively, the findings may provide the basis for
better diagnostic and therapeutic approaches to blood diseases. The
study has been published online in advance in the journal Antioxidants &
Redox Signaling. The print version will be published soon.


========================================================================== "Blood is a juice of very special kind," is what Johann Wolfgang von
Goethe had his Mephistopheles say. The hemoglobin gives blood its red
color and ensures that the erythrocytes (red blood cells) can bind
oxygen for breathing. This is managed by the hemoglobin-bound molecule
"heme," which is a complex composing of a central iron ion and a porphyrin molecule. "The breakdown of erythrocytes results in a pool of so-called
labile, regulatory heme," explains Prof. Dr.

Diana Imhof from the Pharmaceutical Institute of the University of
Bonn. As it can exert toxic effects in high concentrations, the body
tries to keep the amount of heme in check.

It has been known for quite some time that this "labile, regulatory heme" affects the function of biomolecules. The team around Diana Imhof has
now discovered in meticulous detective work which of the many proteins
in the blood is particularly under the control of heme. "Over the last
few years, our research group has established a large database of model peptides," reports Imhof. The peptides are individual protein "snippets"
from which the sometimes huge and complex structures are built. Instead
of studying the giant molecules, the proteins, in their entirety, the researchers first took a shortcut with the snippets.

Researchers searched like profilers for "suspects" The pharmacists
at the University of Bonn proceeded in a similar way to profilers in
thrillers, who draw conclusions about the perpetrator's behavior from
crime scene traces, circumstantial evidence and the type of crime. The researchers used an algorithm to systematically search the database
for protein fragments that might potentially interact with heme. Using
these data, they were able to conclude that the "activated protein C"
(APC) is a particular candidate for heme binding. This enzyme is known
for its anticoagulant and clot-dissolving effect, but can also take over cell-protective and anti- inflammatory tasks.

"So far, the impact of heme on the function of APC has been unknown,"
says Imhof's colleague and lead author of the study, Marie-The're`se
Hopp. The researchers investigated the association with pure compounds in
the test tube and by using blood plasma samples provided by the Institute
of Experimental Hematology and Transfusion Medicine at the University
Hospital Bonn. There, Prof. Dr. Bernd Po"tzsch and Dr. Nasim Shahidi
Hamedani also supported the pharmacists with know-how, APC samples,
test systems and access to specific devices. "We demonstrated that the enzymatic and anticoagulant activity of APC is reduced in the presence
of heme," reports Hopp. For example, if there is too little APC or its
activity is restricted, the risk of a clot forming in the bloodstream increases, thereby causing thrombosis, heart attack or stroke.

Indeed, diseases with an increased incidence of labile heme (hemolytic diseases), such as sickle cell disease, are often associated with
thrombotic complications.

Greater scope than previously assumed "For this reason, the influence
of heme on the enzyme APC is more significant than has probably been
suspected so far," says Imhof. Furthermore, the team discovered that APC
might protect the cells of the inner blood vessel wall like a bodyguard
against the cytotoxic effect of heme. The researchers cultivated human endothelial cells and exposed them to heme. If APC was present at the
same time, the toxic effect of heme on the cells was suppressed.

"We are convinced that this interaction between APC and heme is
significant, because many other blood proteins we were looking for
did not bind heme," says Imhof. It might be worthwhile to further
investigate the impact of labile, regulatory heme on APC in order to
also gain new diagnostic and therapeutically relevant insights regarding
blood coagulation disorders that occur in hemolytic diseases. Imhof:
"The terrain should be explored much more thoroughly than has been the
case to date."

========================================================================== Story Source: Materials provided by University_of_Bonn. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Marie-The're`se Hopp, Nour Alhanafi, Ajay Abisheck Paul George,
Nasim
Shahidi Hamedani, Arijit Biswas, Johannes Oldenburg, Bernd Po"tzsch,
Diana Imhof. Molecular Insights and Functional Consequences of
the Interaction of Heme with Activated Protein C. Antioxidants &
Redox Signaling, 2020; DOI: 10.1089/ars.2019.7992 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200904121315.htm

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