Author
Dipl. Biol. Martina Veith, Prof. Dr. Timm Greulich, Alpha1 Deutschland eV, as published in Alpha1 Journal 2/2022.
„"AAT supports the immune response and plays an important role in the course of inflammation, infection or tissue injury."“
Proteins are essential for our bodies, as they are responsible for a multitude of cellular functions. Some proteins provide the structure of the cell. Others act as transporters for smaller molecules, such as hemoglobin in red blood cells, which carries oxygen to the cell and carries away carbon dioxide. Enzymes are needed to initiate or accelerate biochemical reactions in the body. Antibodies enable the body's immune system to recognize and specifically combat potentially harmful microbes.
Alpha-1-antitrypsin (AAT) is an acute-phase protein. AAT supports the immune response and plays an important role in the course of inflammation, infection, or tissue injury. AAT is primarily produced in the liver and is found in virtually all body tissues. It acts as a protective protein, serving as an important antagonist to endogenous substances that can break down tissue.
Although proteins perform a wide variety of functions, they are all structured according to a basic principle. They consist of various amino acids (building blocks) strung together like beads on a necklace and linked by a peptide bond between the carboxyl group (one end of an amino acid) of the first and the amino group (the other end of an amino acid) of the next. Depending on which of the 20 amino acids are used and in what order they are linked, different proteins are formed. Each protein has a very specific three-dimensional structure. This structure is essential for the protein to perform its specific function within the organism.
The blueprints for proteins are stored in DNA (deoxyribonucleic acid) segments (genes) in the form of a code (genetic code). The genetic code is derived from the sequence in which the four organic bases adenine, thymine, cytosine, and guanine are arranged.
The process from gene to protein is called protein biosynthesis and consists of two main steps: transcription and translation (see Fig. 1 ‚From gene to protein‘).
During transcription (from Latin transcribere = to transcribe), transportable copies (mRNA = messenger RNA) of the DNA segment that codes for the protein are produced in the cell nucleus. For this purpose, the genetic information of the double-stranded DNA is transcribed into single-stranded mRNAs. In the RNA, the base thymine is replaced by the base uracil.
After transcription, the mRNA is transported from the cell nucleus into the cytoplasm and binds to the ribosome, where it is translated. Here, the mRNA serves as a template for linking different amino acids together to form a protein.
Three consecutive bases, also called triplets or codons, code for one amino acid. In addition, there are special combinations (codons) for the beginning (start) and end (stop) of a gene (see Fig. 2, 'Genetic Code Chart'). This code is – with few exceptions – universal: in humans, mice, and bacteria.
The deciphering of the genetic code in 1961 by Nirenberg and Matthaei made it possible to understand the processes of protein biosynthesis at the molecular level, thus forming the foundation of genetic engineering (MW Nirenberg, JHMatthaei, Proc. Natl. Acad. Sci. USA 1961, 47, 1601. 6) Cold Spring Harbor Symposium, Vol. XXXI, 1966, pp. 25-38).
Currently, various groups worldwide are researching diverse applications of 'medical' RNA: this ranges from the treatment of hereditary diseases and cancers to vaccination.
Studies in the field of alpha-1 antitrypsin deficiency also utilize RNA interference (RNAi) to selectively silence genes. RNAi is a natural mechanism in cells used to silence genes. RNA interference is based on the interaction of short RNA fragments with mRNA. As a result, the mRNA is cleaved into multiple fragments, and the information it carries is disrupted. Translation into a protein is prevented. This allows the cell to regulate protein production, as not every cell needs the same proteins at the same time.
This mechanism is being used in a study of patients with alpha-1 antitrypsin deficiency and the Pi*ZZ genotype. In the common Z mutation, alpha-1 antitrypsin is misfolded and cannot diffuse from liver cells into the bloodstream. An artificially produced RNA fragment is intended to inhibit the production of the mutated alpha-1 antitrypsin (Z-AAT) protein, thus preventing the accumulation of misfolded Z proteins in liver cells. The current state of the study looks very promising. (Strnad P, Mandorfer M, et al. Fazirsiran for Liver Disease Associated with Alpha(1)-Antitrypsin Deficiency. N Engl J Med. 2022 Aug 11;387(6):514-524. doi: 10.1056/NEJMoa2205416. Epub 2022 Jun 25.)
Dipl. Biol. Martina Veith, Prof. Dr. Timm Greulich
