Acyl-CoA thioesterase 9 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that is encoded by the human ACOT9

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 ...

. It is a member of the acyl-CoA

thioesterase In biochemistry, thioesterases are enzymes which belong to the esterase family. Esterases, in turn, are one type of the several hydrolases known. Thioesterases exhibit esterase activity (splitting of an ester into an acid and an alcohol, in the ...

superfamily, which is a group of

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

that

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 ...

Coenzyme A Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the Fatty acid metabolism#Synthesis, synthesis and Fatty acid metabolism#.CE.B2-Oxidation, oxidation of fatty acids, and the oxidation of pyruvic acid, pyruvate in the citric ac ...

ester In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...

s. There is no known function, however it has been shown to act as a long-chain thioesterase at low concentrations, and a short-chain thioesterase at high concentrations.

Gene

Locus

The ACOT9 gene is located at p22.11 on

chromosome X The X chromosome is one of the two sex chromosomes in many organisms, including mammals, and is found in both males and females. It is a part of the XY sex-determination system and XO sex-determination system. The X chromosome was named for its u ...

. Located on the minus strand of the chromosome, the start is at 23,721,777 bp and the end is at 23,761,407 bp, which is a span of 39,631

base pairs A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...

Aliases

ACOT9 gene is known primarily for encoding the Acyl-CoA thioesterase 9 protein. Other, less commonly used names for the gene are ACATE2, and MT-ACT48.

Function

The protein encoded by the ACOT9 gene is part of a family of

Acyl-CoA Acyl-CoA is a group of coenzyme A, CoA-based coenzymes that metabolize carboxylic acids. Fatty acyl-CoA's are susceptible to beta oxidation, forming, ultimately, acetyl-CoA. The acetyl-CoA enters the citric acid cycle, eventually forming several e ...

s, which catalyze the

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...

of various

esters of various molecules to the free acid plus CoA. These enzymes have also been referred to in the literature as acyl-CoA hydrolases, acyl-CoA thioester hydrolases, and palmitoyl-CoA hydrolases. The reaction carried out by these

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 ...

s is as follows: CoA ester + H₂O → free acid + coenzyme A These enzymes use the same

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 (aquatic environment), the earthy material that exi ...

s as long-chain acyl-CoA synthetases, but have a unique purpose in that they generate the free acid and CoA, as opposed to long-chain acyl-CoA synthetases, which ligate fatty acids to CoA, to produce the CoA ester. The role of the ACOT- family of enzymes is not well understood; however, it has been suggested that they play a crucial role in regulating the intracellular levels of CoA esters, Coenzyme A, and free fatty acids. Recent studies have shown that Acyl-CoA esters have many more functions than simply an energy source. These functions include

allosteric regulation In the fields of biochemistry and pharmacology an allosteric regulator (or allosteric modulator) is a substance that binds to a site on an enzyme or receptor distinct from the active site, resulting in a conformational change that alters the ...

of enzymes such as

acetyl-CoA carboxylase Acetyl-CoA carboxylase (ACC) is a biotin-dependent enzyme () that catalyzes the irreversible carboxylation of acetyl-CoA to produce malonyl-CoA through its two catalytic activities, biotin carboxylase (BC) and carboxyltransferase (CT). ACC ...

hexokinase A hexokinase is an enzyme that irreversibly phosphorylates hexoses (six-carbon sugars), forming hexose phosphate. In most organisms, glucose is the most important substrate for hexokinases, and glucose-6-phosphate is the most important p ...

IV, and the citrate condensing enzyme. Long-chain acyl-CoAs also regulate opening of

ATP-sensitive potassium channel An ATP-sensitive potassium channel (or KATP channel) is a type of potassium channel that is gated by intracellular nucleotides, ATP and ADP. ATP-sensitive potassium channels are composed of Kir6.x-type subunits and sulfonylurea receptor (S ...

s and activation of Calcium ATPases, thereby regulating

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...

secretion. A number of other cellular events are also mediated via acyl-CoAs, for example signal transduction through

protein kinase C In cell biology, protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and t ...

, inhibition of

retinoic acid Retinoic acid (simplified nomenclature for all-''trans''-retinoic acid) is a metabolite of vitamin A1 (all-''trans''-retinol) that is required for embryonic development, male fertility, regulation of bone growth and immune function. All-''trans ...

-induced apoptosis, and involvement in budding and fusion of the

endomembrane system The endomembrane system is composed of the different membranes (endomembranes) that are suspended in the cytoplasm within a eukaryotic cell. These membranes divide the cell into functional and structural compartments, or organelles. In eukaryote ...

. Acyl-CoAs also mediate protein targeting to various membranes and regulation of

G Protein G proteins, also known as guanine nucleotide-binding proteins, are a Protein family, family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell (biology), ...

α subunits, because they are substrates for protein acylation. In the

mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

, acyl-CoA esters are involved in the acylation of mitochondrial NAD+ dependent

dehydrogenase A dehydrogenase is an enzyme belonging to the group of oxidoreductases that oxidizes a substrate by reducing an electron acceptor, usually NAD+/NADP+ or a flavin coenzyme such as FAD or FMN. Like all catalysts, they catalyze reverse as well as ...

s; because these enzymes are responsible for

amino acid catabolism 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 ap ...

, this acylation renders the whole process inactive. This mechanism may provide metabolic crosstalk and act to regulate the

NADH Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an ade ...

/NAD+ ratio in order to maintain optimal mitochondrial

beta oxidation In biochemistry and metabolism, beta oxidation (also β-oxidation) is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA. Acetyl-CoA enter ...

of fatty acids. The role of CoA esters in

lipid metabolism Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown and storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In ani ...

and numerous other intracellular processes are well defined, and thus it is hypothesized that ACOT- enzymes play a role in modulating the processes these metabolites are involved in.

Homology/Evolution

Orthologs

There are many

ortholog Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a speci ...

s of ACOT9, the house mouse (''Mus musculus'') being one of the most similar, where the ACOT9 gene is found at 72.38cM on chromosome X. The range of orthologs extends to mammals, birds, amphibians, anamorphic fungi, and others.

Paralogs

In mice, which is one of the closest orthologs, ACOT10 is a known paralog of the ACOT9 gene.

Expression

Expression of the ACOT9 is

ubiquitous Omnipresence or ubiquity is the property of being present anywhere and everywhere. The term omnipresence is most often used in a religious context as an attribute of a deity or supreme being, while the term ubiquity is generally used to describ ...

throughout the tissues in humans. Tissues with a value of over 500 in the large-scale analysis of the human transcriptome were the globus pallidus and colorectal adenocarcinoma. The expressed sequence tag (or EST) abundance profile also shows

/near ubiquitous, expression throughout human tissues.

Transcription factors

There are numerous

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...

s throughout the ACOT9 promoter sequence. Some of the notable factors are

heat shock factor In molecular biology, heat shock factors (HSF), are the transcription factors that regulate the expression of the heat shock proteins. A typical example is the heat shock factor of ''Drosophila melanogaster''. Function Heat shock factors (H ...

s and

transcription factor II B Transcription factor II B (TFIIB) is a general transcription factor that is involved in the formation of the RNA polymerase II preinitiation complex (PIC) and aids in stimulating transcription initiation. TFIIB is localised to the nucleus and p ...

(TFIIB) recognition elements.

Secondary structure

There are two regions in the ACOT9 gene sequence that are labeled as BFIT (Brown Fat Inducible Thioesterase) and BACH (Brain Acyl CoA Hydrolase) regions. These regions are part of a HotDog fold

superfamily SUPERFAMILY is a database and search platform of structural and functional annotation for all proteins and genomes. It classifies amino acid sequences into known structural domains, especially into SCOP superfamilies. Domains are functional, str ...

, which has been found to be used in a variety of cell roles. Predictions show there to be various

alpha-helices An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix). The alpha helix is the most common structural arrangement in the secondary structure of proteins. It is also the most extreme type of l ...

throughout the structure, suggesting it is a

transmembrane protein A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently un ...

Interactions

A mitochondrial cleavage site can be found at amino acid 30 in the ACOT9 sequence, and the probability of export to the

is 0.9374. The Acyl-CoA thioesterase 9 protein is estimated to be 60.9% mitochondrial, 21.7%

cytoplasmic The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell and ...

, 8.7% nuclear, 4.3% in the

plasma membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

, and 4.3% in the

endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...

. The ACOT9 protein has been found to interact with the following proteins either experimentally or through co-expression: * C1orf151 * MCTS1 * C1GALT1C1 * FBXW12 * RLIM *

RPS6KA3 protein S6 kinase, 90kDa, polypeptide 3, also s RPS6KA3, is an enzyme that in humans is encoded by the ''RPS6KA3'' gene. Function This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases. This kinase con ...

RAB9A Ras-related protein Rab-9A is a protein that in humans is encoded by the ''RAB9A'' gene. Interactions RAB9A has been shown to interact with RABEPK, TIP47 Mannose-6-phosphate receptor binding protein 1 (M6PRBP1) is a protein which in human ...

UBC The University of British Columbia (UBC) is a Public university, public research university with campuses near University of British Columbia Vancouver, Vancouver and University of British Columbia Okanagan, Kelowna, in British Columbia, Canada ...

* CXorf26 * HCCS