Neuropathy target esterase, also known as patatin-like phospholipase domain-containing protein 6 (PNPLA6), is an

esterase In biochemistry, an esterase is a class of enzyme that splits esters into an acid and an alcohol in a chemical reaction with water called hydrolysis (and as such, it is a type of hydrolase). A wide range of different esterases exist that differ ...

enzyme that in humans is encoded by the ''PNPLA6''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. Neuropathy target esterase is a

phospholipase A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. There are four major classes, termed A, B, C, and D, which are distinguished by the type of reaction which they catalyze: *Phospholipase ...

that deacetylates intracellular

phosphatidylcholine Phosphatidylcholines (PC) are a class of phospholipids that incorporate choline as a headgroup. They are a major component of biological membranes and can easily be obtained from a variety of readily available sources, such as egg yolk or soyb ...

to produce

glycerophosphocholine L-α-Glycerophosphorylcholine (alpha-GPC, choline alfoscerate, ''sn''-glycero-3-phosphocholine) is a natural choline compound found in the brain. It is also a parasympathomimetic acetylcholine precursor which has been investigated for its potent ...

. It is thought to function in neurite outgrowth and process elongation during neuronal differentiation. The protein is anchored to the cytoplasmic face of the

endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...

in both neurons and non-neuronal cells.

Function

Neuropathy target esterase is an enzyme with

phospholipase B Phospholipase B, also known as lysophospholipase, is an enzyme with a combination of both PLA1 and PLA2 activities; that is, it can cleave acyl chains from both the ''sn''-1 and ''sn''-2 positions of a phospholipid. In general, it acts on lysoleci ...

activity: it sequentially hydrolyses both fatty acids from the major membrane lipid

, generating water-soluble glycerophosphocholine. In

eukaryotic The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...

cells, NTE is anchored to the cytoplasmic face of the endoplasmic reticulum membrane. In

mammal A mammal () is a vertebrate animal of the Class (biology), class Mammalia (). Mammals are characterised by the presence of milk-producing mammary glands for feeding their young, a broad neocortex region of the brain, fur or hair, and three ...

s, it is particularly abundant in neurons, the

placenta The placenta (: placentas or placentae) is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas, and waste exchange between ...

, and the kidney. Loss of NTE activity results in abnormally-elevated levels of phosphatidylcholine in the brain and impairment of the

constitutive secretory pathway Constitutive may refer to: * In physics, a constitutive equation is a relation between two physical quantities * In ecology, a constitutive defense is one that is always active, as opposed to an inducible defense * Constitutive theory of statehoo ...

in neurons. In the

kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...

, the expression of neuropathy target esterase is regulated by TonEBP as part of

osmolyte Osmolytes are low-molecular-weight organic compounds that influence the properties of biological fluids. Osmolytes are a class of organic molecules that play a significant role in regulating osmotic pressure and maintaining cellular homeostasis in ...

production when the kidney produces concentrated

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

Clinical significance

Mutations in this gene result in autosomal-recessive spastic paraplegia. The protein is also the target for neurodegeneration induced by

organophosphorus compound Organophosphorus chemistry is the scientific study of the synthesis and properties of organophosphorus compounds, which are organic compounds containing phosphorus. They are used primarily in pest control as an alternative to chlorinated hydrocarbo ...

s and chemical warfare agents. Recessively-inherited mutations in ''NTE'' that substantially reduce its catalytic activity cause a rare form of

hereditary spastic paraplegia Hereditary spastic paraplegia (HSP) is a group of inherited diseases whose main feature is a progressive Gait abnormality, gait disorder. The disease presents with progressive stiffness (spasticity) and contraction in the lower limbs. HSP is als ...

(SPG39), in which distal parts of long spinal

axons An axon (from Greek ἄξων ''áxōn'', axis) or nerve fiber (or nerve fibre: see spelling differences) is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action pot ...

degenerate leading to limb weakness and paralysis.

Organophosphate-induced delayed neuropathy Organophosphate-induced delayed neuropathy (OPIDN), also called organophosphate-induced delayed polyneuropathy (OPIDP), is a neuropathy caused by killing of neurons in the central nervous system, especially in the spinal cord, as a result of acute ...

a paralysing syndrome with distal degeneration of long axons results from poisoning with neuropathic organophosphorus compounds that irreversibly inhibit NTE.

Function

Clinical significance

References

Further reading