Lipoyl synthase is an

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 ...

that belongs to the

radical SAM Radical SAM enzymes belong to a superfamily of enzymes that use an iron-sulfur cluster (4Fe-4S) to reductively cleave S-Adenosyl methionine, ''S''-adenosyl-L-methionine (SAM) to generate a radical (chemistry), radical, usually a 5′-deoxyadenosyl ...

( ''S''-adenosyl methionine) family. Within the radical SAM superfamily, lipoyl synthase is in a sub-family of enzymes that catalyze sulfur insertion reactions. The enzymes in this subfamily differ from general radical SAM enzymes, as they contain two 4Fe-4S clusters. From these clusters, the enzymes obtain the sulfur groups that will be transferred onto the corresponding substrates. This particular enzyme participates in the final step of

lipoic acid Lipoic acid (LA), also known as α-lipoic acid, alpha-lipoic acid (ALA) and thioctic acid, is an organosulfur compound derived from caprylic acid (octanoic acid). ALA, which is made in animals normally, is essential for aerobic metabolism. It i ...

metabolism, transferring two

sulfur Sulfur ( American spelling and the preferred IUPAC name) or sulphur ( Commonwealth spelling) is a chemical element; it has symbol S and atomic number 16. It is abundant, multivalent and nonmetallic. Under normal conditions, sulfur atoms ...

atoms from its 4Fe-4S cluster onto the protein N₆-(octanoyl)lysine through

radical Radical (from Latin: ', root) may refer to: Politics and ideology Politics *Classical radicalism, the Radical Movement that began in late 18th century Britain and spread to continental Europe and Latin America in the 19th century *Radical politics ...

generation. This enzyme is usually localized to 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 ...

. Two organisms that have been extensively studied with regards to this enzyme are ''

Escherichia coli ''Escherichia coli'' ( )Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. is a gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Escherichia'' that is commonly fo ...

'' and ''

Mycobacterium tuberculosis ''Mycobacterium tuberculosis'' (M. tb), also known as Koch's bacillus, 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'' ha ...

.'' It is currently being studied in other organisms including yeast, plants, and humans.

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 semitrivi ...

of this enzyme class is protein N6-(octanoyl)lysine:sulfur sulfurtransferase. Other names in common use include: * LS * LipA * lipoate synthase * protein 6-N-(octanoyl)lysine:sulfur sulfurtransferase.

Structure

The sequence length of ''M. tuberculosis'' lipoyl synthase is approximately 331 amino acids. The structure is composed of 11 α-helices and 7 β sheets, with multiple loop structures connecting the other components. The two Fe-4Sclusters are located within the structure, appearing in three-dimensional cubic shape. A molecule of DTV ((2S,3S)-1,4-Dimercaptobutane-2,3-diol), more commonly known as DTT (

dithiothreitol Dithiothreitol (DTT) is an organosulfur compound with the formula . A colorless compound, it is classified as a dithiol and a diol. DTT is redox reagent also known as Cleland's reagent, after W. Wallace Cleland. The reagent is commonly used in ...

), is also present within the structure. This molecule is responsible for protecting thiol groups from oxidation. The molecule is surrounded by water molecules as well, which form hydrogen bonds with side residues to stabilize the structure. The enzyme's structure is shown.

Mechanism of lipoyl synthase

As previously mentioned, lipoyl synthase is a member of a subfamily of the radical SAM(S-adenosyl methionine) enzyme family, which use a Fe-4Scluster cofactor. This cofactor is used by this enzyme to produce 5'-deoxyadenosyl 5'-radical (5'-dA). Lipoyl synthase itself uses this radical to abstract hydrogens from the 6th and 8th carbons of the protein N₆(octanoyl)lysine substrate. Two sulfurs from one of lipoyl synthase's two Fe-4Sclusters, known as the auxiliary cluster, are then attached to the 6th and 8th carbons in place of the abstracted hydrogens.The protein N6-(octanoyl)lysine substrate is then converted into the protein N₆-(lipoyl)lysine. The figure on the right depicts the lysine interacting with the auxiliary cluster to add one sulfur, which then becomes an Fe-3Scluster. The other Fe-4Scluster is coordinated by the radical SAM motif of the enzyme (CxxxCxxC) and participates in radical SAM characteristic chemistry to activate the substrate for subsequent sulfur insertion. The three substrates of this enzyme are N6-(octanoyl)lysine,

, and

S-adenosyl-L-methionine ''S''-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throug ...

. The three

products Product may refer to: Business * Product (business), an item that can be offered to a market to satisfy the desire or need of a customer. * Product (project management), a deliverable or set of deliverables that contribute to a business solution ...

are N6-(lipoyl)lysine,

L-methionine Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other non-essential amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine play ...

, and 5'-deoxyadenosine. Below displays the overall reaction catalyzed by lipoyl synthase, with the structures of each substrate and product. Lipoyl Synthase mechanism

Importance of lipoyl synthase

This enzyme participates in

metabolism, where it performs the final step in lipoic acid biosynthesis. Lipoic acid is a cofactor that has different functions within different organisms. The

generation in yeast cells increases the number of divisions in the cells as well as protects yeast cells from hydrogen peroxide.

Lipoic acid Lipoic acid (LA), also known as α-lipoic acid, alpha-lipoic acid (ALA) and thioctic acid, is an organosulfur compound derived from caprylic acid (octanoic acid). ALA, which is made in animals normally, is essential for aerobic metabolism. It i ...

is an important co-factor in many enzyme systems, and one of them is the

pyruvate dehydrogenase complex Pyruvate dehydrogenase complex (PDC) is a complex of three enzymes that converts pyruvate into acetyl-CoA by a process called pyruvate decarboxylation. Acetyl-CoA may then be used in the citric acid cycle to carry out cellular respiration, and ...

. Studies that repressed the function of lipoyl synthase in ''Arabidopsis thaliana'' seeds showed that this did not have adverse effects on seed growth and weight, but shortened the generation time as well as the flowering time of the plants. Repression resulted in earlier flowering times and decreased the generation times between seeds by almost 10%.

Possible side effects of lipoyl synthase in plants

Overexpression of this enzyme in sunflower plants has been found to eventually sequester the amount of SAM present in transgenic ''Arabidopsis'' plants. SAM is a molecule that is required in other enzymatic complexes found in this plant as well, as well as the overall structure of the plant, so this sequestration may cause a reduction in the fatty acid biosynthesis in the ''Arabidopsis'' seeds.

References

{{Portal bar, Biology, border=no, Chemistry EC 2.8.1 Enzymes of unknown structure