The enzyme 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 recyc ...

the chemical reaction :(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 (TC ...

, except that an additional methyl group (marked with an asterisk in the above scheme) is present, meaning that citrate 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 ''Mycobacterium tuberculosis'' (M. tb) is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis. First discovered in 1882 by Robert Koch, ''M. tuberculosis'' has an unusual, waxy coating on its c ...

'', 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 bonds by means other than hydrolysis (a substitution reaction) and oxidation, often forming a new double bond or a new ring structure. ...

s, specifically the oxo-acid-lyases, which cleave carbon-carbon bonds. The systematic name 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. Methylisocitrate lyase was discovered in 1976.

Structural studies

As of late 2007, 6 structures have been solved for this class of enzymes, with PDB accession codes , , , , , and . The structure is very similar to that of phosphoenolpyruvate mutase. 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 phosphoenolpyruvate mutase). 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, socia ...

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 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 liq ...

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 In enzymology, a 2-methylcitrate synthase () is an enzyme that catalyzes the chemical reaction :propanoyl-CoA + H2O + oxaloacetate \rightleftharpoons (2R,3S)-2-hydroxybutane-1,2,3-tricarboxylate + CoA The 3 substrates of this enzyme are propan ...

adds propionyl coenzyme A to oxaloacetate, yielding methylcitrate instead of citrate. 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, 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 ...

, a complex cofactor often used to metabolize propionate. The methylcitrate cycle is found in many microorganisms. Methylisocitrate lyase plays a regulatory function in this cycle; it is activated by NAD but inhibited noncompetitively by NADH 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 NAD ...

References

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