Succinyl-CoA ligase DP-formingsubunit beta, mitochondrial is an

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

that in humans is encoded by the ''SUCLG2''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

on chromosome 3. This gene encodes a GTP-specific beta subunit of succinyl-CoA synthetase. Succinyl-CoA synthetase

catalyze Catalysis () is the increase in rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recycles quick ...

s the reversible reaction involving the formation of

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 Alpha-Ketoglutaric acid, α-ketoglutarate ...

and

succinate Succinic acid () is a dicarboxylic acid with the chemical formula (CH2)2(CO2H)2. In living organisms, succinic acid takes the form of an anion, succinate, which has multiple biological roles as a metabolic intermediate being converted into Fuma ...

Alternate splicing Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene may be included ...

results in multiple transcript variants.

Pseudogenes Pseudogenes are nonfunctional segments of DNA that resemble functional genes. Pseudogenes can be formed from both protein-coding genes and non-coding genes. In the case of protein-coding genes, most pseudogenes arise as superfluous copies of fun ...

of this gene are found on chromosomes 5 and 12. rovided by RefSeq, Apr 2010ref 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 Phosphorylation, phosphorylated form or a Dephosphorylati ...

'' gene and a β subunit encoded by either the ''

SUCLA2 Succinyl-CoA ligase DP-formingsubunit beta, mitochondrial (SUCLA2), also known as ADP-forming succinyl-CoA synthetase (SCS-A), is an enzyme that in humans is encoded by the ''SUCLA2'' gene on chromosome 13. Succinyl-CoA synthetase (SCS) is a ...

'' gene or the ''SUCLG2'' gene, which determines the enzyme specificity for either ADP or GDP. SUCLG2 is the SCS variant containing the ''SUCLG2''-encoded β subunit.

Amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

sequence alignment of the two β subunit types reveals a homology of ~50% identity, with specific regions conserved throughout the sequences. ''SUCLG2'' is located on chromosome 3 and contains 14

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 sequence ...

Function

As a subunit of SCS, SUCLG2 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, cholesterol biosynthesis. It also takes a similar role in the ketone bodies synthesis (ketogenesis) pathway of the liver. In the ...

, accompanied by the

substrate-level phosphorylation Substrate-level phosphorylation is a metabolism reaction that results in the production of ATP or GTP supported by the energy released from another high-energy bond that leads to phosphorylation of ADP or GDP to ATP or GTP (note that the rea ...

of GDP to GTP, as a step in the tricarboxylic acid (TCA) cycle. The GTP generated is then consumed in

anabolic Anabolism () is the set of metabolic pathways that construct macromolecules like DNA or RNA from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catab ...

pathways. However, since GTP is not transported through the

inner mitochondrial membrane The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space. Structure The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. T ...

in mammals and other higher organisms, it must be recycled within the matrix. In addition, SUCLG2 may function in ATP generation in the absence of SUCLA2 by complexing with the mitochondrial nucleotide diphosphate

kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...

, nm23-H4, and thus compensate for SUCLA2 deficiency. The reverse reaction generates succinyl-CoA from succinate to fuel

ketone body Ketone bodies are water-soluble molecules or compounds 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 acet ...

and

heme Heme (American English), or haem (Commonwealth English, both pronounced /Help:IPA/English, hi:m/ ), is a ring-shaped iron-containing molecule that commonly serves as a Ligand (biochemistry), ligand of various proteins, more notably as a Prostheti ...

synthesis. While SCS is ubiquitously expressed, SUCLG2 is predominantly expressed in tissues involved in biosynthesis, including

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

and

kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...

. SUCLG2 has also been detected in the micro

vasculature In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart an ...

of the brain, likely to support its growth. Notably, both SUCLA2 and SUCLG2 are absent in

astrocyte Astrocytes (from Ancient Greek , , "star" and , , "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 en ...

microglia Microglia are a type of glia, glial cell located throughout the brain and spinal cord of the central nervous system (CNS). Microglia account for about around 5–10% of cells found within the brain. As the resident macrophage cells, they act as t ...

, and

oligodendrocyte Oligodendrocytes (), also known as oligodendroglia, are a type of neuroglia whose main function is to provide the myelin sheath to neuronal axons in the central nervous system (CNS). Myelination gives metabolic support to, and insulates the axons ...

s in the

brain The brain is an organ (biology), 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 ...

; thus, in order to acquire succinate to continue the TCA cycle, these cells may instead synthesize succinate through

GABA GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...

metabolism of α-ketoglutarate or ketone body metabolism of succinyl-CoA.

Clinical significance

Though mitochondrial DNA (mtDNA) depletion syndrome has been largely attributed to SUCLA2 deficiency, SUCLG2 may play a more crucial role in mtDNA maintenance, as it functions to compensate for SUCLA2 deficiency and its absence results in decreased mtDNA and OXPHOS-dependent growth. SUCLG2 may also play a role in clearing

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...

amyloid-beta Amyloid beta (Aβ, Abeta or beta-amyloid) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor prot ...

1–42 (Aβ1–42) in

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

(AD) and, thus, reducing neuronal death.

References

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Structure

Function

Clinical significance

See also

References