The

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 ...

methylisocitrate lyase ()

catalyzes 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 recycl ...

the

chemical reaction A chemical reaction is a process that leads to the chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the positions of electrons in the forming and break ...

:(2''S'',3''R'')-3-hydroxybutane-1,2,3-tricarboxylate

\rightleftharpoons

pyruvate + succinate The reaction is similar to that of

isocitrate lyase Isocitrate lyase (), or ICL, is an enzyme in the glyoxylate cycle that catalyzes the cleavage of isocitrate to succinate and glyoxylate. Together with malate synthase, it bypasses the two decarboxylation steps of the tricarboxylic acid cycle (T ...

, except that an additional methyl group (marked with an asterisk in the above scheme) is present, meaning that

citrate Citric acid is an organic compound with the chemical formula HOC(CO2H)(CH2CO2H)2. It is a colorless weak organic acid. It occurs naturally in citrus fruits. In biochemistry, it is an intermediate in the citric acid cycle, which occurs in t ...

is replaced by methylcitrate and

glyoxylate Glyoxylic acid or oxoacetic acid is an organic compound. Together with acetic acid, glycolic acid, and oxalic acid, glyoxylic acid is one of the C2 carboxylic acids. It is a colourless solid that occurs naturally and is useful industrially. Str ...

pyruvate Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell. Pyruvic aci ...

. In fact, in some bacteria such as '' Mycobacterium tuberculosis'', isocitrate lyase actually plays the role of methylisocitrate lyase. This enzyme belongs to the family of

lyase In biochemistry, a lyase is an enzyme that catalyzes the breaking (an elimination reaction) of various chemical bond A chemical bond is a lasting attraction between atoms or ions that enables the formation of molecules and crystals. The bon ...

s, specifically the oxo-acid-lyases, which cleave carbon-carbon bonds. 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 (2S,3R)-3-hydroxybutane-1,2,3-tricarboxylate pyruvate-lyase (succinate-forming). Other names in common use include 2-methylisocitrate lyase, MICL, and (2S,3R)-3-hydroxybutane-1,2,3-tricarboxylate pyruvate-lyase. This enzyme participates in

propanoate metabolism Propionic acid (, from the Greek words πρῶτος : ''prōtos'', meaning "first", and πίων : ''píōn'', meaning "fat"; also known as propanoic acid) is a naturally occurring carboxylic acid with chemical formula CH3CH2CO2H. It is a liqu ...

. Methylisocitrate lyase was discovered in 1976.

Structural studies

As of late 2007, 6

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 a ...

have been solved for this class of enzymes, with

PDB PDB may refer to: * Chess Problem Database Server (PDB Server) * 1,4-Dichlorobenzene (paradichlorobenzene) * Party of German-speaking Belgians, (German: '), a political party and predecessor of the ProDG * PDB (Palm OS), a container format for reco ...

accession codes , , , , , and . The structure is very similar to that of

phosphoenolpyruvate mutase In enzymology, a phosphoenolpyruvate mutase () is an enzyme that catalyzes the chemical reaction :phosphoenolpyruvate \rightleftharpoons 3-phosphonopyruvate Hence, this enzyme has one substrate, phosphoenolpyruvate (PEP), and one product, 3 ...

. A homotetrameric biological unit is composed of beta barrels with the active site at one end. A magnesium ion is present in the active site, and an active-site "gating loop" moves inward toward it when substrate binds and away with no substrate bound, thus shielding the reaction from solvent. Helices are present all around the beta barrels; in particular, a C-terminal helical domain splits off from the barrel to interact with the barrel of a neighboring subunit, in a "helix swapping" motif (see

). The following still shot from a

ribbon A ribbon or riband is a thin band of material, typically cloth but also plastic or sometimes metal, used primarily as decorative binding and tying. Cloth ribbons are made of natural materials such as silk, cotton, and jute and of synthetic mater ...

kinemage A kinemage (short for kinetic image) is an interactive graphic scientific illustration. It often is used to visualize molecules, especially proteins although it can also represent other types of 3-dimensional data (such as geometric figures, soc ...

shows one subunit from the crystal structure 1MUM, which includes a magnesium ion (gray) but no substrate; helices are red while loops are white and beta strands are green.

Function

Methylisocitrate lyase is used in the methylcitrate cycle, a modified version of the

Krebs 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 ...

that metabolizes

propionyl Propionic acid (, from the Greek words πρῶτος : ''prōtos'', meaning "first", and πίων : ''píōn'', meaning "fat"; also known as propanoic acid) is a naturally occurring carboxylic acid with chemical formula CH3CH2CO2H. It is a liqu ...

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 ...

instead of

acetyl coenzyme A Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized for ...

. The enzyme 2-methylcitrate synthase adds propionyl coenzyme A to

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 ...

, yielding methylcitrate instead of

. But isomerizing methylcitrate to methylisocitrate and then subjecting it to MICL regenerates succinate, which proceeds as in the Krebs cycle, and pyruvate, which is easily metabolized by other pathways (e.g. decarboxylated to form acetyl coenzyme A and oxidized in the Krebs cycle). This allows catabolism of propionic acid—and, using

beta oxidation In biochemistry and metabolism, beta-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, which enters the citric acid cyc ...

, other fatty acids with odd numbers of carbons—without relying on

coenzyme B12 Cyanocobalamin is a form of vitamin used to treat vitamin deficiency except in the presence of cyanide toxicity. The deficiency may occur in pernicious anemia, following surgical removal of the stomach, with fish tapeworm, or due to bowel c ...

, a complex cofactor often used to metabolize propionate. The methylcitrate cycle is found in many

microorganism A microorganism, or microbe,, ''mikros'', "small") and ''organism'' from the el, ὀργανισμός, ''organismós'', "organism"). It is usually written as a single word but is sometimes hyphenated (''micro-organism''), especially in olde ...

s. Methylisocitrate lyase plays a regulatory function in this cycle; it is activated by NAD but inhibited noncompetitively by

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 aden ...

and

NADPH Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require NADP ...

References

{{Portal bar, Biology, border=no EC 4.1.3 Enzymes of known structure