Acyl-protein thioesterases are

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 ...

s that cleave off

lipid Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...

modifications on proteins, located on the

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 ...

atom of

cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...

residues linked via a

thioester In organic chemistry, thioesters are organosulfur compounds with the molecular structure . They are analogous to carboxylate esters () with the sulfur in the thioester replacing oxygen in the carboxylate ester, as implied by the thio- prefix ...

bond. Acyl-protein thioesterases are part of the α/β hydrolase superfamily of proteins and have a conserved

catalytic triad A catalytic triad is a set of three coordinated amino acid residues that can be found in the active site of some enzymes. Catalytic triads are most commonly found in hydrolase and transferase enzymes (e.g. proteases, amidases, esterases, aminoac ...

. For that reason, acyl-protein thioesterases are also able to

hydrolyze Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysis ...

oxygen Oxygen is a chemical element; it has chemical symbol, symbol O and atomic number 8. It is a member of the chalcogen group (periodic table), group in the periodic table, a highly reactivity (chemistry), reactive nonmetal (chemistry), non ...

-linked ester bonds.

Function

Acyl-protein thioesterases are involved in the depalmitoylation of proteins, meaning they cleave off

palmitoyl In molecular biology, 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 typic ...

modifications on proteins' cysteine residues. Cellular targets include trimeric G-alpha proteins,

ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by Gating (electrophysiol ...

s and

GAP-43 Growth Associated Protein 43 (GAP43) is a protein encoded by the ''GAP43'' gene in humans. GAP43 is called a "growth" or "plasticity" protein because it is expressed at high levels in neuronal growth cones during developmentReferenced within : ...

. Moreover, human acyl-protein thioesterases 1 and 2 have been identified as major components in controlling the palmitoylation cycle of the

oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

Ras. Depalmitoylation of Ras by acyl-protein thioesterases potentially reduces Ras'

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

to endomembranes, allowing it to be palmitoylated again at the

Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic Cell (biology), cells. Part of the endomembrane system in the cytoplasm, it protein targeting, packages proteins ...

and to be directed to the

plasma membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

. Acyl-protein thioesterases, therefore, are thought to correct potential mislocalization of Ras.

Known enzymes

Currently fully validated human acyl-protein thioesterases are APT1 and APT2 which share 66%

sequence homology Sequence homology is the homology (biology), biological homology between DNA sequence, DNA, RNA sequence, RNA, or Protein primary structure, protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments ...

. Additionally there are a handful of putative acyl-protein thioesterases reported, including the ABHD17 enzyme family. In the lysosome,

PPT1 Palmitoyl-protein thioesterase 1 (PPT-1), also known as palmitoyl-protein hydrolase 1, is an enzyme that in humans is encoded by the PPT1 gene. Function PPT-1 a member of the palmitoyl protein thioesterase family. PPT-1 is a small glycoprote ...

of the

palmitoyl protein thioesterase Palmitoyl protein hydrolase/thioesterases is an enzyme (EC 3.1.2.22) that removes thioester-linked fatty acyl groups such as palmitate from modified cysteine residues in proteins or peptides during lysosomal degradation. It catalyzes the rea ...

family has similar enzymatic activity as acyl-protein thioesterases.

Structure

Acyl-protein thioesterases feature 3 major structural components that determine protein function and

substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (aquatic environment), the earthy material that exi ...

processing: 1. A conserved, classical

to break

ester In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...

and

bonds; 2. A long

hydrophobic In chemistry, hydrophobicity is the chemical property of a molecule (called a hydrophobe) that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, thu ...

substrate tunnel to accommodate the palmitoyl moiety, as identified in the crystal structures of human acyl-protein thioesterase 1, human acyl-protein thioesterase 2 and ''Zea mays'' acyl-protein thioesterase 2; 3. A lid- loop that covers the

catalytic site In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate, the ''binding si ...

, is highly flexible and is a main factor determining the enzyme's product release rate. APT mechanism and product release

Inhibition

The involvement in controlling the localization of the

oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

Ras has made acyl-protein thioesterases potential

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

drug targets.

Inhibition Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransm ...

of acyl-protein thioesterases is believed to increase mislocalization of Ras at the cell's

membranes A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. B ...

, eventually leading to a collapse of the Ras cycle. Inhibitors for acyl-protein thioesterases have been specifically targeting the hydrophobic substrate tunnel, the catalytic site serine or both.

Research

Current approaches to study the biological activity of Acyl-protein Thioesterases include

proteomics Proteomics is the large-scale study of proteins. Proteins are vital macromolecules of all living organisms, with many functions such as the formation of structural fibers of muscle tissue, enzymatic digestion of food, or synthesis and replicatio ...

, monitoring the trafficking of microinjected fluorescent substrates, the use of cell-permeable substrate mimetics, and cell permeable small molecule fluorescent chemical tools.

References

{{Reflist, 32em Cell biology Lysophospholipases Peripheral membrane proteins Post-translational modification