In molecular biology, hydroxymethylglutaryl-CoA synthase or HMG-CoA synthase is an enzyme which catalyzes the reaction in which acetyl-CoA condenses with

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 ...

to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). This reaction comprises the second step in the

mevalonate Mevalonic acid (MVA) is a key organic compound in biochemistry; the name is a contraction of dihydroxymethylvalerolactone. The carboxylate anion of mevalonic acid, which is the predominant form in biological environments, is known as ''mevalonate ...

-dependent isoprenoid biosynthesis pathway. HMG-CoA is an intermediate in both cholesterol synthesis and

ketogenesis Ketogenesis is the biochemical process through which organisms produce ketone bodies by breaking down fatty acids and ketogenic amino acids. The process supplies energy to certain organs, particularly the brain, heart and skeletal muscle, under ...

. This reaction is overactivated in patients with

diabetes mellitus type 1 Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for ...

if left untreated, due to prolonged insulin deficiency and the exhaustion of substrates for gluconeogenesis and the

TCA 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 ...

, notably

oxaloacetate Oxaloacetic acid (also known as oxalacetic acid or OAA) is a crystalline organic compound with the chemical formula HO2CC(O)CH2CO2H. Oxaloacetic acid, in the form of its conjugate base oxaloacetate, is a metabolic intermediate in many processes ...

. This results in shunting of excess acetyl-CoA into the ketone synthesis pathway via HMG-CoA, leading to the development of

diabetic ketoacidosis Diabetic ketoacidosis (DKA) is a potentially life-threatening complication of diabetes mellitus. Signs and symptoms may include vomiting, abdominal pain, deep gasping breathing, increased urination, weakness, confusion and occasionally loss of ...

.
The 3 substrates of this enzyme are acetyl-CoA, H₂O, and

, whereas its two

products Product may refer to: Business * Product (business), an item that serves as a solution to a specific consumer problem. * Product (project management), a deliverable or set of deliverables that contribute to a business solution Mathematics * Produ ...

are (''S'')-3-hydroxy-3-methylglutaryl-CoA and CoA. In humans, the protein is encoded by the ''HMGCS1'' gene on chromosome 5.

Classification

This enzyme belongs to the family of

transferase A transferase is any one of a class of enzymes that catalyse the transfer of specific functional groups (e.g. a methyl or glycosyl group) from one molecule (called the donor) to another (called the acceptor). They are involved in hundreds of ...

s, specifically those acyltransferases that convert acyl groups into alkyl groups on transfer.

Nomenclature

The

systematic name A systematic name is a name given in a systematic way to one unique group, organism, object or chemical substance, out of a specific population or collection. Systematic names are usually part of a nomenclature. A semisystematic name or semitrivial ...

of this enzyme class is acetyl-CoA:acetoacetyl-CoA C-acetyltransferase (thioester-hydrolysing, carboxymethyl-forming). Other names in common use include ''(''S'')-3-hydroxy-3-methylglutaryl-CoA acetoacetyl-CoA-lyase'', ''(CoA-acetylating)'', ''3-hydroxy-3-methylglutaryl CoA synthetase'', ''3-hydroxy-3-methylglutaryl coenzyme A synthase'', ''3-hydroxy-3-methylglutaryl coenzyme A synthetase'', ''3-hydroxy-3-methylglutaryl-CoA synthase'', ''3-hydroxy-3-methylglutaryl-coenzyme A synthase'', ''beta-hydroxy-beta-methylglutaryl-CoA synthase'', ''HMG-CoA synthase'', ''acetoacetyl coenzyme A transacetase'', ''hydroxymethylglutaryl coenzyme A synthase'', and ''hydroxymethylglutaryl coenzyme A-condensing enzyme''.

Mechanism

HMG-CoA synthase contains an important

catalytic Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...

cysteine residue that acts as a nucleophile in the first step of the reaction: the acetylation of the

enzyme Enzymes () are proteins that act as biological catalysts 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 products ...

by acetyl-CoA (its first substrate) to produce an acetyl-enzyme

thioester In organic chemistry, thioesters are organosulfur compounds with the functional group . They are analogous to carboxylate esters () with the sulfur in the thioester playing the role of the linking oxygen in the carboxylate ester, as implied by t ...

, releasing the reduced coenzyme A. The subsequent

nucleophilic attack In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...

(its second substrate) leads to the formation of

HMG-CoA β-Hydroxy β-methylglutaryl-CoA (HMG-CoA), also known as 3-hydroxy-3-methylglutaryl coenzyme A, is an intermediate in the mevalonate and ketogenesis pathways. It is formed from acetyl CoA and acetoacetyl CoA by HMG-CoA synthase. The research of ...

Biological role

This enzyme participates in 3

metabolic pathways In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical re ...

: synthesis and degradation of ketone bodies,

valine, leucine and isoleucine degradation A branched-chain amino acid (BCAA) is an amino acid having an aliphatic side-chain with a branch (a central carbon atom bound to three or more carbon atoms). Among the proteinogenic amino acids, there are three BCAAs: leucine, isoleucine, and va ...

, and

butanoate metabolism Butyric acid (; from grc, βούτῡρον, meaning "butter"), also known under the systematic name butanoic acid, is a straight-chain alkyl carboxylic acid with the chemical formula CH3CH2CH2CO2H. It is an oily, colorless liquid with an unple ...

Species distribution

HMG-CoA synthase occurs in eukaryotes, archaea, and certain

bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typically a few micrometr ...

Eukaryotes

vertebrates Vertebrates () comprise all animal taxa within the subphylum Vertebrata () (chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, with c ...

, there are two different

isozymes In biochemistry, isozymes (also known as isoenzymes or more generally as multiple forms of enzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isozymes usually have different kinetic parameters (e.g. dif ...

of the enzyme (

cytosolic 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 ...

and mitochondrial); in humans the cytosolic form has only 60.6% amino acid identity with the mitochondrial form of the enzyme. HMG-CoA is also found in other eukaryotes such as

insects Insects (from Latin ') are pancrustacean hexapod invertebrates of the class Insecta. They are the largest group within the arthropod phylum. Insects have a chitinous exoskeleton, a three-part body (head, thorax and abdomen), three pairs of j ...

plants Plants are predominantly photosynthetic eukaryotes of the kingdom Plantae. Historically, the plant kingdom encompassed all living things that were not animals, and included algae and fungi; however, all current definitions of Plantae exclude ...

, and

fungi A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from ...

Cytosolic

The cytosolic form is the starting point of the mevalonate pathway, which leads to

cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...

and other sterolic and isoprenoid compounds.

Mitochondrial

The mitochondrial form is responsible for the biosynthesis of ketone bodies. The

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 ...

for the mitochondrial form of the enzyme has three sterol regulatory elements in the 5' flanking region.Goldstein J.L., Brown M.S. (1990) Regulation of the mevalonate pathway. Nature 343, 425-430 These elements are responsible for decreased

transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...

of the

message A message is a discrete unit of communication intended by the source for consumption by some recipient or group of recipients. A message may be delivered by various means, including courier, telegraphy, carrier pigeon and electronic bus. A ...

responsible for enzyme synthesis when dietary cholesterol is high in animals: the same is observed for 3-hydroxy-3-methylglutaryl-CoA and the low density lipoprotein receptor.

Bacteria

, isoprenoid precursors are generally synthesised via an alternative, non-mevalonate pathway, however a number of

Gram-positive In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. Gram-positive bact ...

pathogen 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 germ ...

s utilise a mevalonate pathway involving HMG-CoA synthase that is parallel to that found in eukaryotes.

Structural studies

As of late 2007, 4

structures A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such as ...

have been solved for this class of enzymes, with PDB accession codes , , , and .

External links

References

* {{DEFAULTSORT:Hmg-Coa Synthase EC 2.3.3 Protein families Human proteins