Cytidine monophospho-''N''-acetylneuraminic acid hydroxylase (Cmah) is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
that is encoded by the ''CMAH''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
In most mammals, the enzyme
hydroxylates N-acetylneuraminic acid (Neu5Ac), producing
N-glycolylneuraminic acid (Neu5Gc).
Neu5Ac
''N''-Acetylneuraminic acid (Neu5Ac or NANA) is the predominant sialic acid found in human cells, and many mammalian cells. Other forms, such as N-Glycolylneuraminic acid, may also occur in cells.
This residue is negatively charged at physiolog ...
and
Neu5Gc are mammalian glycans that compose the
glycocalyx
The glycocalyx, also known as the pericellular matrix, is a glycoprotein and glycolipid covering that surrounds the cell membranes of bacteria, epithelial cells, and other cells. In 1970, Martinez-Palomo discovered the cell coating in animal cel ...
, especially in
sialoglycoproteins, which are part of the
sialic acid Sialic acids are a class of alpha-keto acid sugars with a nine-carbon backbone.
The term "sialic acid" (from the Greek for saliva, - ''síalon'') was first introduced by Swedish biochemist Gunnar Blix in 1952. The most common member of this ...
family.
The ''CMAH'' equivalent in humans is a
pseudogene
Pseudogenes are nonfunctional segments of DNA that resemble functional genes. Most arise as superfluous copies of functional genes, either directly by DNA duplication or indirectly by reverse transcription of an mRNA transcript. Pseudogenes are ...
(CMAHP); there is no detectable Neu5Gc in normal human tissue.
This deficiency has a number of proposed effects on humans, including increased brain growth and improved self-recognition by the human
immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as Tumor immunology, cancer cells and objects such ...
.
Incorporation of Neu5Gc from red meat and dairy into human tissues has been linked to chronic disease, including
type-2 diabetes and
chronic inflammation.
Discovery
The
biosynthesis pathway of Neu5Gc from Neu5Ac was discovered by Shaw and Schauer in 1988,
while the
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...
and
DNA sequences
A nucleic acid sequence is a succession of bases signified by a series of a set of five different letters that indicate the order of nucleotides forming alleles within a DNA (using GACT) or RNA (GACU) molecule. By convention, sequences are usu ...
for Neu5Gc, Neu5Ac, and ''CMAHP'' were described by Irie ''et al''. in 1998.
Evolution
Genomic analyses indicate that ''CMAH'' genes are present only in
deuterostomes, some unicellular
algae
Algae ( , ; : alga ) are any of a large and diverse group of photosynthetic, eukaryotic organisms. The name is an informal term for a polyphyletic grouping that includes species from multiple distinct clades. Included organisms range from ...
and some
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...
.
''CMAH'' relatives have been lost in many other deuterostome lineages, including
tunicates
A tunicate is a marine invertebrate animal, a member of the subphylum Tunicata (). It is part of the Chordata, a phylum which includes all animals with dorsal nerve cords and notochords (including vertebrates). The subphylum was at one time ...
, many groups of fish, the
axolotl, most reptiles, and all birds.
Among mammals, the gene is missing or nonfunctional in New World monkeys, the European hedgehog, ferrets, some bats, the sperm whale, and the platypus.
These animals lacking a functional ''CMAH'' gene do not express Neu5Gc.
The absence of Neu5Gc in humans is due to a 92-bp
deletion
Deletion or delete may refer to:
Computing
* File deletion, a way of removing a file from a computer's file system
* Code cleanup, a way of removing unnecessary variables, data structures, cookies, and temporary files in a programming language
* ...
of an
exon
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequenc ...
of the human gene ''CMAH''
''.'' Sequences encoding mouse, pig, and chimpanzee ''CMAH'' have been examined using
cDNA
In genetics, complementary DNA (cDNA) is DNA synthesized from a single-stranded RNA (e.g., messenger RNA (mRNA) or microRNA (miRNA)) template in a reaction catalyzed by the enzyme reverse transcriptase. cDNA is often used to express a speci ...
cloning techniques and were found to be highly similar.
However, the
homologous
Homology may refer to:
Sciences
Biology
*Homology (biology), any characteristic of biological organisms that is derived from a common ancestor
*Sequence homology, biological homology between DNA, RNA, or protein sequences
* Homologous chrom ...
human cDNA differs from these cDNAs by a 92-bp deletion in the 5' region.
This deletion, corresponding to exon 5 of the mouse hydroxylase gene, causes a
frameshift mutation
A frameshift mutation (also called a framing error or a reading frame shift) is a genetic mutation caused by indels (gene insertion, insertions or genetic deletion, deletions) of a number of nucleotides in a DNA sequence that is not divisible by ...
and premature termination of the
polypeptide chain
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides ...
in humans.
Neu5Gc seems to be undetectable in human tissues because the truncated version of human hydroxylase
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.
mRNA is created during the ...
cannot encode for an active enzyme.
The deletion that deactivated this gene occurred approximately 3.2
mya
Mya may refer to:
Brands and product names
* Mya (program), an intelligent personal assistant created by Motorola
* Mya (TV channel), an Italian Television channel
* Midwest Young Artists, a comprehensive youth music program
Codes
* Burmese ...
, after the divergence of humans from the African
great apes
The Hominidae (), whose members are known as the great apes or hominids (), are a taxonomic family of primates that includes eight extant species in four genera: '' Pongo'' (the Bornean, Sumatran and Tapanuli orangutan); '' Gorilla'' (the ...
, and quickly swept to
fixation in the human population.
The lineage of this pseudogene in humans indicates another deep split in Africa dating to 2.9 mya, with a complex subsequent history.
Sexual selection
Sexual selection is a mode of natural selection in which members of one biological sex choose mates of the other sex to mate with (intersexual selection), and compete with members of the same sex for access to members of the opposite sex (in ...
may have contributed to the fixation of nonfunctional ''CMAH'' in humans.
This hypothesis has been tested in mice, with females carrying nonfunctional ''CMAH'' exhibiting reproductive incompatibility with males carrying functional ''CMAH'' due to anti-Neu5Gc
antibodies migrating to the female reproductive tract and destroying Neu5Gc-positive sperm.
Function in other mammals
Sialic acids such as Neu5Ac and Neu5Gc are terminal components of the carbohydrate chains of
glycoconjugates involved in
ligand–receptor,
cell–cell, and cell–pathogen interactions.
Neu5Gc has been shown to be involved in a variety of processes in mice, including
protein metabolism,
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellular ...
,
metabolism
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run c ...
of most organic molecules, and immunity.
Cat AB blood group
The
blood type
A blood type (also known as a blood group) is a classification of blood, based on the presence and absence of antibodies and inherited antigenic substances on the surface of red blood cells (RBCs). These antigens may be proteins, carbohydrat ...
for a cat is mostly covered by the AB blood group system, determined by the CMAH alleles a cat possess. The majority A type seems to be dominant over the recessive B type, which is only found with a higher frequency in some breeds. An "AB" type seems to be expressed by a third recessive allele.
Function in humans
Neu5Gc has been found in normal human tissue, with larger amounts found in fetal
and cancerous
tissues. Studies suggest that Neu5Gc could be an excellent cancer cell marker.
Since Neu5Gc can only be made by functional ''CMAH,'' which is not present in humans, researchers have searched for alternative sources of Neu5Gc in humans.
Current research indicates that Neu5Gc is incorporated into human tissues through consumption of red meats and dairy.
This incorporation process involves
macropinocytosis, delivery to the
lysosome
A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane ...
, and export of free Neu5Gc to the
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
via the sialin transporter.
Because Neu5Gc differs from Neu5Ac by only one oxygen, it is handled like a native sialic acid by human
biochemical pathways.
The immune system does not work the same way, however; all humans have varying amounts of a diverse spectrum of anti-Neu5Gc antibodies.
If Neu5Gc is constantly being incorporated into tissues due to a diet heavy in red meats and dairy, anti-Neu5Gc antibodies cause chronic inflammation, especially in blood vessels and the linings of hollow organs.
These sites are also common places for
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually ...
and
epithelial carcinomas, both of which are associated with red meat and dairy consumption and are aggravated by chronic inflammation.
Red meat ingestion and chronic inflammation have also been associated with diseases like type-2 diabetes and age-dependent
macular degeneration
Macular degeneration, also known as age-related macular degeneration (AMD or ARMD), is a medical condition which may result in blurred or no vision in the center of the visual field. Early on there are often no symptoms. Over time, however, som ...
, so Neu5Gc may be linked to the development of these disorders as well.
Recent data suggests that the
hypoxic conditions in
carcinomas
Carcinoma is a malignancy that develops from epithelial cells. Specifically, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that arises from cells originating in the endodermal, mesodermal ...
can up-regulate the expression of the lysosomal sialic acid transporter necessary for Neu5Gc incorporation into human tissues.
In addition,
growth factors
A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for re ...
may activate enhanced macropinocytosis, which can increase Neu5Gc incorporation.
Studies have shown that fetal tissues are also capable of taking up Neu5Gc from maternal dietary sources, which may explain elevated levels of Neu5Gc in the human fetus.
The presence of Neu5Gc in various
biotherapeutics derived from animal products may impact human health and is still being studied.
Some complications could include
immune hypersensitivity reactions, reduced
half-life
Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable at ...
of the biotherapeutic in circulation,
immune complex
An immune complex, sometimes called an antigen-antibody complex or antigen-bound antibody, is a molecule formed from the binding of multiple antigens to antibodies. The bound antigen and antibody act as a unitary object, effectively an antigen o ...
formation, increase of Neu5Gc antibody concentration, enhanced
immunoreactivity against the biotherapeutic polypeptide, and directly loading more Neu5Gc into tissues.
Implications for human evolution
Pseudogenes such as ''CMAH'' can be used to study
allele
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
fixation and
demographic history.
Analyses of ''CMAH''
haplotype
A haplotype ( haploid genotype) is a group of alleles in an organism that are inherited together from a single parent.
Many organisms contain genetic material ( DNA) which is inherited from two parents. Normally these organisms have their DNA or ...
diversity have been used to examine human demographic history during the
Plio-Pleistocene
The Plio-Pleistocene is an informally described geological pseudo-period, which begins about 5 million years ago (Mya) and, drawing forward, combines the time ranges of the formally defined Pliocene and Pleistocene epochs—marking from about 5& ...
.
The functional loss of ''CMAH'' after the divergence of humans from the great apes has several implications for its role in human development, including less constrained brain growth and increased running endurance, two traits thought to be important to human evolution.
In most mammals, ''CMAH''
expression is down-regulated in the brain, and experimental up-regulation of ''CMAH'' is lethal in mice.
Experimental ''CMAH'' loss in mice increases running endurance and decreases muscle fatigue, which could have been beneficial to ancestral ''
Homo
''Homo'' () is the genus that emerged in the (otherwise extinct) genus '' Australopithecus'' that encompasses the extant species ''Homo sapiens'' (modern humans), plus several extinct species classified as either ancestral to or closely relat ...
'' during the gene's fixation.
Implications for pathogenicity
The loss of Neu5Gc in humans may have contributed to resistance to generalist
pathogens
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a ger ...
and increased
pathogenicity
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a ger ...
of human-specific pathogens.
Human-specific
cholera, which employs host sialic acids to trigger a gastrointestinal response, preferentially uses Neu5Ac and is inhibited by Neu5Gc.
Nonfunctionialization of ''CMAH'' has made humans more susceptible to some
viruses
A virus is a submicroscopic infectious agent that replicates only inside the living cells
Cell most often refers to:
* Cell (biology), the functional basic unit of life
Cell may also refer to:
Locations
* Monastic cell, a small room ...
by decreasing sialic acid diversity.
Viruses that bind to Neu5Ac before entering the cell are enhanced by the high density of Neu5Ac, which would be reduced if other sialic acids were present on human
cell membranes
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (th ...
.
For example, the most serious form of
malaria
Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or deat ...
in humans, ''
P. falciparum
''Plasmodium falciparum'' is a Unicellular organism, unicellular protozoan parasite of humans, and the deadliest species of ''Plasmodium'' that causes malaria in humans. The parasite is transmitted through the bite of a female ''Anopheles'' mosqu ...
,'' binds to Neu5Ac on the membrane of
red blood cells
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
.
In contrast to these negative effects, losing ''CMAH'' should actually protect humans against any virus that targets Neu5Gc, such as those that cause
diarrheal diseases
Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...
in livestock
, ''E. coli'' K99,
transmissible gastroenteritis coronavirus (TGEV),
and
simian virus 40
SV40 is an abbreviation for simian vacuolating virus 40 or simian virus 40, a polyomavirus that is found in both monkeys and humans. Like other polyomaviruses, SV40 is a DNA virus that has the potential to cause tumors in animals, but most often ...
(SV40).
References
Further reading
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