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Succinyl-CoA ligase DP-formingsubunit beta, mitochondrial (SUCLA2), also known as ADP-forming succinyl-CoA synthetase (SCS-A), 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 in humans is encoded by the ''SUCLA2''
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 ...
on chromosome 13.
Succinyl-CoA synthetase Succinyl-coenzyme A, abbreviated as succinyl-CoA () or SucCoA, is a thioester of succinic acid and coenzyme A. Sources It is an important intermediate in the citric acid cycle, where it is synthesized from α-ketoglutarate by α-ketoglutarate de ...
(SCS) is a
mitochondrial matrix In the mitochondrion, the matrix is the space within the inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contains the mitochondrial DNA, ri ...
enzyme that acts as a
heterodimer In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...
, composed of an invariant alpha
subunit Subunit may refer to: *Subunit HIV vaccine, a class of HIV vaccine *Protein subunit, a protein molecule that assembles with other protein molecules *Monomer, a molecule that may bind chemically to other molecules to form a polymer *Sub-subunit, a ...
and a
substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (locomotion), the surface over which an organism lo ...
-specific beta subunit. The protein encoded by this gene is an
ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals, men's professional tennis governing body * American Technical Publishers, employee-owned publishing company * ', a Danish pension * Armenia Tree Project, non ...
-specific SCS beta subunit that dimerizes with the SCS alpha subunit to form SCS-A, an essential component of the
tricarboxylic acid cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and protein ...
. SCS-A
hydrolyze Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysis ...
s ATP to convert
succinyl-CoA Succinyl-coenzyme A, abbreviated as succinyl-CoA () or SucCoA, is a thioester of succinic acid and coenzyme A. Sources It is an important intermediate in the citric acid cycle, where it is synthesized from α-ketoglutarate by α-ketoglutarate de ...
to
succinate Succinic acid () is a dicarboxylic acid with the chemical formula (CH2)2(CO2H)2. The name derives from Latin ''succinum'', meaning amber. In living organisms, succinic acid takes the form of an anion, succinate, which has multiple biological ro ...
. Defects in this gene are a cause of
myopathic In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. This results in muscular weakness. ''Myopathy'' means muscle disease (Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This mean ...
mitochondrial DNA depletion syndrome Mitochondrial DNA depletion syndrome (MDS or MDDS), or Alper's disease, is any of a group of autosomal recessive disorders that cause a significant drop in mitochondrial DNA in affected tissues. Symptoms can be any combination of myopathic, hep ...
. 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 ...
of this gene has been found on chromosome 6. rovided by RefSeq, Jul 2008ref name="entrez"/>


Structure

SCS, also known as succinyl CoA ligase (SUCL), is a heterodimer composed of a catalytic α subunit encoded by the ''
SUCLG1 Succinyl-CoA ligase DP-formingsubunit alpha, mitochondrial is an enzyme that in humans is encoded by the ''SUCLG1'' gene. Structure The enzyme encoded by SUCLG1 can exist in either a phosphorylated form or a dephosphorylated form. In the deph ...
'' gene and a β subunit encoded by either the ''SUCLA2'' gene or the ''
SUCLG2 Succinyl-CoA ligase DP-formingsubunit beta, mitochondrial is an enzyme that in humans is encoded by the ''SUCLG2'' gene on chromosome 3. This gene encodes a GTP-specific beta subunit of succinyl-CoA synthetase. Succinyl-CoA synthetase catalyzes ...
'' gene, which determines the enzyme specificity for either ADP or GDP. SUCLA2 is the SCS variant containing the ''SUCLA2''-encoded β subunit.
Amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
sequence alignment of the two β subunit types reveals a homology of ~50% identity, with specific regions conserved throughout the sequences. ''SUCLA2'' is located on chromosome 13 and contains 13
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 ...
s.


Function

As a subunit of SCS, SUCLA2 is a mitochondrial matrix enzyme that catalyzes the reversible conversion of succinyl-CoA to succinate and
Acetoacetyl CoA Acetoacetyl CoA is the precursor of HMG-CoA in the mevalonate pathway, which is essential for cholesterol biosynthesis. It also takes a similar role in the ketone bodies synthesis (ketogenesis) pathway of the liver. In the ketone bodies digestion ...
, accompanied by the
substrate-level phosphorylation Substrate-level phosphorylation is a metabolism reaction that results in the production of ATP or GTP by the transfer of a phosphate group from a substrate directly to ADP or GDP. Transferring from a higher energy (whether phosphate group atta ...
of ADP to ATP, as a step in the tricarboxylic acid (TCA) cycle. The ATP generated is then consumed in
catabolic Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lipids ...
pathways. Since substrate-level phosphorylation does not require oxygen for ATP production, this reaction can rescue cells from cytosolic ATP depletion during
ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems ...
. The reverse reaction generates succinyl-CoA from succinate to fuel
ketone body Ketone bodies are water-soluble molecules that contain the ketone groups produced from fatty acids by the liver (ketogenesis). Ketone bodies are readily transported into tissues outside the liver, where they are converted into acetyl-CoA (acetyl- ...
and
heme Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver. In biochemical terms, heme is a coordination complex "consis ...
synthesis. While SCS is ubiquitously expressed, SUCLA2 is predominantly expressed in catabolic tissues reliant on ATP as their main energy source, including the
heart The heart is a muscular organ found in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon diox ...
,
brain The brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head ( cephalization), usually near organs for special ...
, and
skeletal muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of m ...
. Within the brain, SUCLA2 is found exclusively in
neuron A neuron, neurone, or nerve cell is an membrane potential#Cell excitability, electrically excitable cell (biology), cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous ...
s; meanwhile, both SUCLA2 and SUCLG2 are absent in
astrocyte Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of e ...
s,
microglia Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune ...
, and
oligodendrocyte Oligodendrocytes (), or oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons in the central nervous system of jawed vertebrates, equivalent to the function performed by Schwann cells in th ...
s. In order to acquire succinate to continue the TCA cycle, these cells may instead synthesize succinate through GABAmetabolism of α-ketoglutarate or ketone body metabolism of succinyl-CoA.


Clinical significance

Mutations in the SUCLA2 gene are associated with mitochondrial DNA (mtDNA) depletion syndrome. Symptoms include early-onset
low muscle tone Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases a ...
, severe muscular atrophy,
scoliosis Scoliosis is a condition in which a person's spine has a sideways curve. The curve is usually "S"- or "C"-shaped over three dimensions. In some, the degree of curve is stable, while in others, it increases over time. Mild scoliosis does not t ...
, movement disorders such as dystonia and
hyperkinesia Hyperkinesia refers to an increase in muscular activity that can result in excessive abnormal movements, excessive normal movements, or a combination of both. Hyperkinesia is a state of excessive restlessness which is featured in a large variet ...
,
epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...
, and growth retardation. Because succinic acid cannot be made from succinyl coa, treatment is with oral succinic acid, which allows the Krebs cycle and electron transport chain to function correctly. Other treatments for managing symptoms include exercises to promote mobility and respiratory assistance,
baclofen Baclofen, sold under the brand name Lioresal among others, is a medication used to treat muscle spasticity such as from a spinal cord injury or multiple sclerosis. It may also be used for hiccups and muscle spasms near the end of life. It is ...
to treat dystonia and
hyperkinesia Hyperkinesia refers to an increase in muscular activity that can result in excessive abnormal movements, excessive normal movements, or a combination of both. Hyperkinesia is a state of excessive restlessness which is featured in a large variet ...
, and antiepileptic drugs for seizures. There is a relatively high incidence of a specific SUCLA2 mutation in the
Faroe Islands The Faroe Islands ( ), or simply the Faroes ( fo, Føroyar ; da, Færøerne ), are a North Atlantic archipelago, island group and an autonomous territory of the Danish Realm, Kingdom of Denmark. They are located north-northwest of Scotlan ...
due to a
founder effect In population genetics, the founder effect is the loss of genetic variation that occurs when a new population is established by a very small number of individuals from a larger population. It was first fully outlined by Ernst Mayr in 1942, usi ...
. This particular mutation is often associated with early lethality. Two additional founder mutations have been discovered in the Scandinavian population, in addition to the known SUCLA2 founder mutation in the Faroe Islands. These patients show a higher variability in outcomes with several patients with SUCLA2
missense mutation In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Substitution of protein from DNA mutations Missense m ...
surviving into adulthood. This variability suggests that SUCLA2 missense mutations may be associated with residual enzyme activity.
Coenzyme Q10 Coenzyme Q, also known as ubiquinone and marketed as CoQ10, is a coenzyme family that is ubiquitous in animals and most bacteria (hence the name ubiquinone). In humans, the most common form is coenzyme Q10 or ubiquinone-10. It is a 1,4-ben ...
and antioxidants have been used to treat mitochondrial DNA depletion syndrome, but there is currently no evidence that these treatments result in clinical benefit. Mutations in the ''SUCLA2'' gene leading to SUCLA2 deficiency result in Leigh's or a Leigh-like syndrome with the onset of severe
hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases ...
,
muscular atrophy Muscle atrophy is the loss of skeletal muscle mass. It can be caused by immobility, aging, malnutrition, medications, or a wide range of injuries or diseases that impact the musculoskeletal or nervous system. Muscle atrophy leads to muscle weaknes ...
, sensorineural hearing impairment, and often death in early childhood.


See also

*
Succinyl-CoA synthetase Succinyl-coenzyme A, abbreviated as succinyl-CoA () or SucCoA, is a thioester of succinic acid and coenzyme A. Sources It is an important intermediate in the citric acid cycle, where it is synthesized from α-ketoglutarate by α-ketoglutarate de ...
*
SUCLG1 Succinyl-CoA ligase DP-formingsubunit alpha, mitochondrial is an enzyme that in humans is encoded by the ''SUCLG1'' gene. Structure The enzyme encoded by SUCLG1 can exist in either a phosphorylated form or a dephosphorylated form. In the deph ...
*
SUCLG2 Succinyl-CoA ligase DP-formingsubunit beta, mitochondrial is an enzyme that in humans is encoded by the ''SUCLG2'' gene on chromosome 3. This gene encodes a GTP-specific beta subunit of succinyl-CoA synthetase. Succinyl-CoA synthetase catalyzes ...


References


Further reading

* * * * * * * * {{refend


External links


GeneReview/NCBI/NIH/UW entry on SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form, with Mild Methylmalonic Aciduria