UNWANTED PROTEINS
The nucleus of most human cells contains a person’s unique DNA It is arranged in 23 chains of chromosomes and there are 3 million pairs of 4 nucleotides. 98 percent of the DNA encodes the directions for turning a fertilized egg into a being. Two percent encode 20,000 genes, pairs of nucleotides that can range in size from as a few hundred paired nucleotides long to as many as a length of more than a million nucleotides. Each gene, using messenger RNA, directs the cell to make a certain protein. Proteins are “molecules that perform an array of functions.” Some, for example, catalyze metabolic reactions; others provide structure or transport molecules from one location to another. Biologically proteins are sequences of amino acids that have folded into a specific structure.
“All genes are not expressed in each cell: different sets of genes are active in different types of cells. Nerve cells express genes different from those expressed by muscle cells or liver cells.”
How do cells prevent over production of certain proteins?
“The Nobel Laureates in Physiology or Medicine for 2006, American scientists Andrew Fire and Craig Mello, discovered a fundamental mechanism of gene regulation. They have shown that double-stranded RNA molecules can silence a gene by elimination of the mRNA corresponding to that gene. This is called RNA interference (RNAi) and occurs in both plants and animals.”(1)
“Victor Ambros and Gary Ruvkun were awarded the 2024 Nobel Prize in Physiology or Medicine for their discovery of microRNA:
MicroRNAs are tiny RNA molecules that regulate gene activity in cells, including how much of a protein is synthesized. They play a critical role in development and how organisms function.
The discovery of microRNA revealed a new mechanism of gene regulation and helped us understand how different types of cells form, even though they all contain the same genes.” (2)
“Ubiquitization” is a way our body destroys unwanted proteins.
(Ubiquitin is a 76 amino-acid residue protein that seems to be everywhere and earmarks some proteins for degradation.)
Cereblon (CRBN) is a protein that can form a complex with ubiquitin, and form E3 ubiquitin ligase. The compound tags proteins that need to be destroyed for the cell's health, and is a key to embryonic development.
Ubiquitination is a three-step enzymatic cascade involving E1, E2, and E3 enzymes Posttranslational modification of proteins via ubiquitination determines their activation, translocation, dysregulation, or degradation. This process also targets a large number of cellular proteins, affecting all biological pathways involved in the cell cycle, development, growth, and differentiation
Thalidomide and lenalidomide bind to and inactivate cereblon. The inactivation allows the ubiquitin complex to degrade the transcription factors." And that explained the drug's tendency to cause birth defects, but not its ability to block cancer growth.
When lenalidomide binds to cereblon, it can
trigger the destruction of two transcription factors that are overactive in
multiple myeloma cells. The result: cancer growth is shut down, halting the
progress of the disease. (4)
Neomorph is a San Diego based startup that is “attempting to advance the science of targeted protein degradation to destroy ‘undruggable’ proteins and cure disease.
The TP53 gene, which resides on chromosome 17p13 and encodes the p53 protein, is the most frequent target for mutation in human cancer, with greater than half of all tumors exhibiting mutation at this locus (Vogelstein et al. 2000; Petitjean et al. 2007b).
RAS genes, which are commonly mutated in cancer, may drive
tumor growth beyond their well-known role in signaling at the cell surface.
Mutant RAS genes
are the second most frequently mutated genes in cancer and are /key drivers of some
of the deadliest cancers, including nearly all pancreatic cancers, half of
colorectal cancers, and one-third of lung cancers. Mutant RAS proteins promote
the development and growth of tumors by activating specific proteins at the
cell surface, creating a constant stream of signals telling cells to grow.
Molecular glues are small molecules that stick to target proteins and change the way they interact with other proteins. This can include using the target protein to be marked for destruction by Ubiquitin ligase, part of the cell’s normal garbage-disposal pathway.” (5)
ADDENDUM
Proteins are chains of amino acids that have folded into a special shape. Glutamic acid is one of the amino acids creatures use to form proteins. In mitochondria glutamic acid turns into glutamate and becomes a neurotransmitter, a chemical that helps nerve cells in the brain send and receive information from other cells.
Thalidomide, a synthetic derivative of glutamic acid, was synthesized in 1953 by Swiss Pharmaceuticals and marketed in 1957 by the German company--Chemie Grünenthal. It was sold (among other things) as a medicine that caused deep sleep with no hangover and that alleviated morning sickness. By the end of the 1950s the chemical was marketed by 14 pharmaceutical firms in countries of Europe, Asia, Australia, the Americas, and Africa. It was never approved in the U.S. because the company that marketed the drug, didn't satisfy the "safety concerns of the FDA drug reviewer. She was troubled because it caused neuropathy in rabbits and previous research had shown that drugs that irritated nerves in adults could cause deformities in fetal rabbits." In 1961, two physicians, William G. McBride, MD of Australia and Widulind Lenz, MD noted birth defects that were associated with thalidomide use by pregnant women. By 1961 12,000 children had been damaged and the drug was withdrawn from the market.
. In 1965, thalidomide was shown to effectively treat painful skin lesions that resulted from the inflammatory complications of leprosy (Franks et al., 2004) and the drug was being used to treat a variety of diseases with various degrees of success. In 2006, THALOMID® in combination with dexamethasone was approved for treatment of multiple myeloma (Moehler et al., 2006; Palumbo et al., 2008). (6)
Researchers have shown that lenalidomide, a derivative of thalidomide, killed multiple myeloma cells by disabling overactive switches called transcription factors. Transcription factors are proteins that bind to genes and increase their activity. Cancers are often driven by over activity of these molecular switches.
1600 transcription factors regulate the transcription of genetic material from DNA to messenger RNA and play a role in cell division, cell growth, and cell death.
A number of terrible brain diseases are caused by an accumulation of abnormal proteins. The conditions include Kuru, Mad Cow disease, and (per Stanley Prusiner) Alzheimer's, ALS, and Parkinson's disease.
“We think the abnormal protein that causes these diseases are sometimes ingested and sometimes the result of a mutation of PRNP, The gene that codes for the prion protein in humans. The function of normal prion protein (PrP) is not fully understood, but it may play a role in cell signaling.”
Prions are proteins that adopt alternative conformations which are self propagating. (Prusner)\
They are “infectious” because they can induce normal proteins (PrP) to misfold into their abnormal shape. This misfolded protein, called PrPSc, then accumulates in the brain and causes damage to brain cells and neurodegenerative diseases in animals and humans. The diseases are transmissible and typically have a long incubation period (years to decades) followed by rapid progression of symptoms.
There is currently no cure or effective treatment for prion diseases.
1. https://www.nobelprize.org/prizes/medicine/2006/popular-information/#:~:text=%E2%80%9Cfor%20their%20discovery%20of%20RNA,fundamental%20mechanism%20of%20gene%20regulation.
2. https://www.google.com/search?client=firefox-b-1-e&q=nobel+prize+micro+rnahttps://en.wikipedia.org
4. https://pmc.ncbi.nlm.nih.gov/articles/PMC5574216/#:~:text=CRBN%20has%20an%20important%20role,influences%20cell%20peration%20and%20apoptosis.rolif
5. https://neomorph.com/index.html#science
https://pmc.ncbi.nlm.nih.gov/articles/PMC9910052/
6. https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/thalidomide View chapterExplore book Thalidomide BY K. Ghoreishi, in Encyclopedia of Toxicology (Fourth Edition), 2024
wiki Transcription_factor
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