Monolysocardiolipin acyltransferase (MLCL AT-1) is a mitochondrial

acyltransferase Acyltransferase is a type of transferase enzyme that acts upon acyl groups. Examples include: * Glyceronephosphate O-acyltransferase * Lecithin-cholesterol acyltransferase *Long-chain-alcohol O-fatty-acyltransferase In enzymology, a long-chain ...

that facilitates the remodeling of

monolysocardiolipin Monolysocardiolipin (MLCL) is a phospholipid with three fatty acid chains located in the inner membrane of mitochondria. MLCL is normally present as part of the metabolic cycle of mitochondrial lipids, such as cardiolipin. It is remodeled by th ...

(MLCL) into

cardiolipin Cardiolipin (IUPAC name 1,3-bis(''sn''-3’-phosphatidyl)-''sn''-glycerol) is an important component of the inner mitochondrial membrane, where it constitutes about 20% of the total lipid composition. It can also be found in the membranes of most ...

History

In 1990, biologists Michael Schlame and Bernd Rustow observed the deacylation of cardiolipin into MLCL, which was then converted back into cardiolipin by a protein using linoleoyl

coenzyme A Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All genomes sequenced to date encode enzymes that use coenzyme A as a subs ...

, derived from

phosphatidylcholine Phosphatidylcholines (PC) are a class of phospholipids that incorporate choline as a headgroup. They are a major component of biological membranes and can be easily obtained from a variety of readily available sources, such as egg yolk or so ...

. However, acyltransferase activities involved in the reacylation of MLCL had not been identified or characterized in any mammalian tissue until 1999, by the Hatch lab at the

University of Manitoba The University of Manitoba (U of M, UManitoba, or UM) is a Canadian public research university in the province of Manitoba.rat Rats are various medium-sized, long-tailed rodents. Species of rats are found throughout the order Rodentia, but stereotypical rats are found in the genus ''Rattus''. Other rat genera include '' Neotoma'' ( pack rats), '' Bandicota'' (bandico ...

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 ...

mitochondria. In 2003, the same lab purified and characterized an MLCL acyltransferase in

pig The pig (''Sus domesticus''), often called swine, hog, or domestic pig when distinguishing from other members of the genus ''Sus'', is an omnivorous, domesticated, even-toed, hoofed mammal. It is variously considered a subspecies of ''Sus ...

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

mitochondria, and by comparing this protein against a human protein database, they identified a

sequenced In genetics and biochemistry, sequencing means to determine the primary structure (sometimes incorrectly called the primary sequence) of an unbranched biopolymer. Sequencing results in a symbolic linear depiction known as a sequence which succi ...

but uncharacterized human protein as the enzyme responsible in 2009.

Function

MLCL AT-1 catalyzes the transfer of the

fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...

chain attached to a coenzyme A molecule to an available

hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydrox ...

group on MLCL, producing cardiolipin. This lipid remodeling is separate from the cardiolipin synthesis pathway, and is essential to maintain its unique

unsaturated Saturation, saturated, unsaturation or unsaturated may refer to: Chemistry * Saturation, a property of organic compounds referring to carbon-carbon bonds **Saturated and unsaturated compounds **Degree of unsaturation **Saturated fat or fatty acid ...

fatty acyl composition. MLCL AT-1 typically utilizes linoleoyl coenzyme A, preferred to oleoyl coenzyme A, which is preferred to

palmitoyl Palmitoylation is the covalent attachment of fatty acids, such as palmitic acid, to cysteine (''S''-palmitoylation) and less frequently to serine and threonine (''O''-palmitoylation) residues of proteins, which are typically membrane proteins. ...

coenzyme A.

Activity during apoptosis

MLCL AT-1 activity increases in cells cardiac

myoblast Myogenesis is the formation of skeletal muscular tissue, particularly during embryonic development. Muscle fibers generally form through the fusion of precursor myoblasts into multinucleated fibers called ''myotubes''. In the early development o ...

cells exposed to

2-deoxyglucose 2-Deoxy--glucose is a glucose molecule which has the 2- hydroxyl group replaced by hydrogen, so that it cannot undergo further glycolysis. As such; it acts to competitively inhibit the production of glucose-6-phosphate from glucose at the phos ...

-induced apoptosis. MLCL AT-1 activity also increases in a rat model of spontaneously hypertensive

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...

. Since cardiolipin content is significantly diminished in 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. ...

during apoptosis, the increase of lipid remodeling by MLCL AT-1 may be an effort of the cell to maintain normal cardiolipin levels.

Similarity to mitochondrial trifunctional protein

MLCL AT-1 is completely identical to the 59-kDa

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

end of

mitochondrial trifunctional protein Mitochondrial trifunctional protein (MTP) is a protein attached to the inner mitochondrial membrane which catalyzes three out of the four steps in beta oxidation. MTP is a hetero-octamer composed of four alpha and four beta subunits: * HADHA * HAD ...

HADHA Trifunctional enzyme subunit alpha, mitochondrial also known as hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit is a protein that in humans is encoded by the ''HADHA'' gene. Mutati ...

, suggesting the possibility that the two proteins may be the product of alternative splicing of the same gene. MLCL AT-1 is likely a splice variant of the alpha subunit of MTP.

Hormone interaction

Treatment with

thyroxine File:Thyroid_system.svg, upright=1.5, The thyroid system of the thyroid hormones T3 and T4 rect 376 268 820 433 Thyroid-stimulating hormone rect 411 200 849 266 Thyrotropin-releasing hormone rect 297 168 502 200 Hypothalamus rect 66 216 38 ...

, a

thyroid hormone File:Thyroid_system.svg, upright=1.5, The thyroid system of the thyroid hormones T3 and T4 rect 376 268 820 433 Thyroid-stimulating hormone rect 411 200 849 266 Thyrotropin-releasing hormone rect 297 168 502 200 Hypothalamus rect 66 216 38 ...

, can produce an almost two-fold increase in MLCL AT-1 activity.

References

{{reflist, 2 Enzymes