Organophosphate

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Editor-In-Chief: Henry A. Hoff

Overview

An organophosphate (sometimes abbreviated OP) is the general name for esters of phosphoric acid. Phosphates with at least one phosphorus-carbon bond are probably the most pervasive organophosphorus compounds. Many of the most important biochemicals are organophosphates, including DNA and RNA as well as many cofactors that are essential for life. Organophosphates are also the basis of many insecticides, herbicides, and nerve gases. Organophosphates are widely used as solvents, plasticizers, and EP additives.

Introduction

Organophosphates are widely employed both in natural and synthetic applications because of the ease with which organic groups can be linked together. Being a triprotic acid, phosphoric acid can form triesters whereas carboxylic acids only form monoesters. Esterification entails the attachment of organic groups to phosphorus through oxygen linkers.

Alcohol phosphates

The precursors to such esters are alcohols. Encompassing many thousands of natural and synthetic compounds, alcohols are diverse and widespread.

OP(OH)3 + ROH → OP(OH)2(OR) + H2O
OP(OH)2(OR) + R'OH → OP(OH)(OR)(OR') + H2O
OP(OH)(OR)(OR') + R"OH → OP(OR)(OR')(OR") + H2O

The phosphate esters bearing OH groups are acidic and partially deprotonated in aqueous solution. For example DNA and RNA are polymers of the type [PO2(OR)(OR')-]n. Polyphosphates also form esters. An important example of an ester of a polyphosphate is ATP, which is the monoester of triphosphoric acid (H5P3O10).

Alcohols can be detached from phosphate esters by hydrolysis, which is the reverse of the above reactions. For this reason, phosphate esters are common carriers of organic groups in biosynthesis.

Saccharide phosphates

Monosaccharides and oligosaccharides are water soluble. Some saccharides such as pentose sugars are involved in the pentose phosphate pathway. It is a process that serves to generate NADPH and the synthesis of pentose (5-carbon) sugars. There are two distinct phases in the pathway. The first is the oxidative phase, in which NADPH is generated, and the second is the non-oxidative synthesis of 5-carbon sugars. This pathway is an alternative to glycolysis. While it does involve oxidation of glucose, its primary role is anabolic rather than catabolic. It is also used to generate hydrogen peroxide for phagocytes.[1]

Lipid phosphates

Lipid signaling involves G-protein coupled receptors to which lysophosphatidic acid (LPA) binds, through which sphingosine-1-phosphate (S1P) acts, and platelet-activating factor (PAF) signals. The key event of diacylglycerol (DAG) signaling is the hydrolysis of phosphatidylinositol (4,5)-bisphosphate (PIP2) to DAG and inositol triphosphate (IP3). IP3 is soluble and diffuses freely into the cytoplasm. It can be recognised by the inositol triphosphate receptor (IP3R). IP3 contributes to the activation of protein kinase C (PKC).[2][3]

Lysophosphatidic acid (LPA) is an intermediate in the synthesis of phosphatidic acid (PA). ENPP2 functions as a phospholipase, which catalyzes the transformation of lysophosphatidylcholine into LPA in ECF.[4] LPA has been detected in plasma, ascitic fluid, follicular fluid, and aqueous humor.[4]

Nucleotides

Nucleotides such as orotidine 5'-monophosphate (OMP) range in size from 176 Da (OMP) to 523 Da (GTP). The purine nucleotides involved in RNA or DNA synthesis include: inosine monophosphate (IMP), adenosine triphosphate (ATP), and guanosine triphosphate (GTP). The pyrimidine nucleotides involved include OMP, cytidine triphosphate (CTP), uridine triphosphate (UTP), and thymidine triphosphate (TTP) for DNA in place of UTP. Although rare, higher phosphates do occur such as adenosine tetraphosphate (Ap4) 587 Da. The deoxyribonucleotides have a 'd' in front, like dCTP, except for the thymidine deoxyribonucleotides.

Cofactors

Many organophosphate cofactors are involved in the synthesis of amino acids and nucleotides, including nicotinamide adenine dinucleotide phosphate (NADP) 744 Da and flavin adenine dinucleotide (FAD) 785 Da.

One of the coenzymes essential for the synthesis of amino acids is nicotinamide adenine dinucleotide (NAD) 663 Da. Besides assembling NAD+ de novo from simple amino acid precursors, cells also salvage preformed compounds containing nicotinamide. The three natural compounds containing the nicotinamide ring and used in these salvage metabolic pathways are nicotinic acid (Na), nicotinamide (Nam) and nicotinamide riboside (NR).[5] These compounds are also produced within cells, when the nicotinamide group is released from NAD+ in ADP-ribose transfer reactions. Indeed, the enzymes involved in these salvage pathways appear to be concentrated in the cell nucleus, which may compensate for the high level of reactions that consume NAD+ in this organelle.[6] Nicotinamide mononucleotide adenylyl transferase 1 (NMNAT1) (EC 2.7.7.1) catalyzes a key step of NAD synthesis.[7] It has a nuclear localization signal (NLS).[7] NMNAT1 may be a substrate for nuclear kinases.[7]

Organophosphate pesticides

In health, agriculture, and government, the word "organophosphates" refers to a group of insecticides or nerve agents acting on the enzyme acetylcholinesterase (the pesticide group Carbamates also act on this enzyme, but through a different mechanism). The term is used often to describe virtually any organic phosphorus(V)-containing compound, especially when dealing with neurotoxins. Many of the so called organophosphates contain C-P bonds. For instance, sarin is O-isopropyl methylphosphonofluoridate, which is formally derived from HP(O)(OH)2, not phosphoric acid. Also many compounds which are derivatives of phosphinic acid are used as organic phosphorus containing neurotoxin.

Organophosphate pesticides (as well as Sarin and VX nerve gas) irreversibly inactivate acetylcholinesterase, which is essential to nerve function in insects, humans, and many other animals. Organophosphate pesticides affect this enzyme in varied ways, and thus in their potential for poisoning. For instance, parathion, one of the first OPs commercialized, is many times more potent than malathion, an insecticide used in combatting the Mediterranean fruit fly (Med-fly) and West Nile Virus-transmitting mosquitoes.

Organophosphate pesticides degrade rapidly by hydrolysis on exposure to sunlight, air, and soil, although small amounts can be detected in food and drinking water. Their ability to degrade made them an attractive alternative to the persistent organochlorine pesticides, such as DDT, aldrin and dieldrin. Although organophosphates degrade faster than the organochlorines, they have greater acute toxicity, posing risks to people who may be exposed to large amounts (see the Toxicity section below).

Commonly used organophosphates have included Parathion, Malathion, Methyl parathion, Chlorpyrifos, Diazinon, Dichlorvos, Phosmet, Azinphos methyl.

Organophosphate neurotoxins

Organophosphate neurotoxins have a mixed impact on human society and agriculture, ranging from potentially beneficial insecticides to necrogens for warfare.

History of nerve gases

Early pioneers in the field include Jean Louis Lassaigne (early 1800s) and Philip de Clermount (1854). In 1932, German chemist Willy Lange and his graduate student, Gerde von Krueger, first described the cholinergic nervous system effects of organophosphates, noting a choking sensation and a dimming of vision after exposure. This discovery later inspired German chemist Gerhard Schrader at company I.G. Farben in the 1930s to experiment with these compounds as insecticides. Their potential use as chemical warfare agents soon became apparent, and the Nazi government put Schrader in charge of developing organophosphate (in the broader sense of the word) nerve gases. Schrader's laboratory discovered the G series of weapons, which included Sarin, Tabun, and Soman. The Nazis produced large quantities of these compounds, though did not use them during World War II (likely because they feared the Allies possessed similar weapons). British scientists experimented with an cholinergic organophosphate of their own, called diisopropylfluorophosphate (DFP), during the war. The British later produced VX nerve gas, which was many times more potent than the G series, in the early 1950s.

After World War II, American companies gained access to some information from Schrader's laboratory, and began synthesizing organophosphate pesticides in large quantities. Parathion was among the first marketed, followed later by malathion and azinphosmethyl. The popularity of these insecticides increased after many of the organochlorine insecticides like DDT, dieldrin, and heptachlor were banned in the 1970s.

Structural features of organophosphate neurotoxins

Effective organophosphate neurotoxins have the following structural features:

  • A terminal oxygen connected to phosphorus by a double bond, i.e. a phosphoryl group,
  • Two lipophilic groups bonded to the phosphorus,
  • A leaving group bonded to the phosphorus, often a halide.

Terminal oxygen vs. terminal sulfur

Thiophosphoryl compounds, those bearing the P=S functionality, are much less toxic than related phosphoryl derivatives, which includes as sarin, VX and tetraethyl pyrophosphate. Thiophosphoryl compound is not active inhibitor acetylcholinesterase in either mammals or insects, in mammals the animals metabolism tends to remove lipophilic side groups from the phosphorus atom while an insect tends to oxidise the compound so removing the terminal sulfur and replacing it with a terminal oxygen which causes the compound to be more able to act as an acetylcholinesterase inhibitor.

Fine tuning

Within these requirements, a large number of different lipophilic and leaving groups have been used. The variation of these groups is one means of fine tuning the toxicity of the compound. A good example of this chemistry are the P-thiocyanate compounds which use an aryl (or alkyl) group and an alkylamino group as the lipophilic groups. The thiocyanate is the leaving group.

File:FcPthiocyanate2.jpg
One of the products of the reaction of Fc2P2S4 with dimethyl cyanamide

It was claimed in a German patent that the reaction of 1,3,2,4-dithiadiphosphetane 2,4-disulfides with dialkyl cyanamides formed plant protection agents which contained six membered (P-N=C-N=C-S-) rings. It has been proven in recent times by the reaction of diferrocenyl 1,3,2,4-dithiadiphosphetane 2,4-disulfide (and Lawesson's reagent) with dimethyl cyanamide that, in fact, a mixture of several different phosphorus-containing compounds is formed. Depending on the concentration of the dimethyl cyanamide in the reaction mixture, either a different six membered ring compound (P-N=C-S-C=N-) or a nonheterocylic compound (FcP(S)(NR2)(NCS)) is formed as the major product; the other compound is formed as a minor product.

In addition, small traces of other compounds are also formed in the reaction. It is unlikely that the ring compound (P-N=C-S-C=N-) {or its isomer} would act as a plant protection agent, but (FcP(S)(NR2)(NCS)) compounds can act as nerve poisons in insects.

Organophosphate poisoning

Many organophosphates are potent neurotoxins, functioning by inhibiting the action of acetylcholinesterase (AChE) in nerve cells. They are one of the most common causes of poisoning worldwide, and are frequently intentionally used in suicides in agricultural areas. Their toxicity is not limited to the acute phase, however, and chronic effects have long been noted. Neurotransmitters such as acetylcholine (which is affected by organophosphate pesticides) are profoundly important in the brain's development, and many OPs have neurotoxic effects on developing organisms even from low levels of exposure.

See also

Phosphate homeostasis

References

  1. Immunology at MCG 1/cytotox
  2. Irvine RF (1992). "Inositol lipids in cell signalling". Curr Opin Cell Biol. 4 (2): 212–19. PMID 1318060.
  3. Nishizuka Y (1995). "Protein kinase C and lipid signaling for sustained cellular responses". FASEB J. 9 (7): 484–96. PMID 7737456.
  4. 4.0 4.1 Ferry G, Tellier E, Try A, Grés S, Naime I, Simon MF, Rodriguez M, Boucher J, Tack I, Gesta S, Chomarat P, Dieu M, Raes M, Galizzi JP, Valet P, Boutin JA, Saulnier-Blache JS (2003). "Autotaxin is released from adipocytes, catalyzes lysophosphatidic acid synthesis, and activates preadipocyte proliferation. Up-regulated expression with adipocyte differentiation and obesity". J Biol Chem. 278 (20): 18162–9. doi:10.1074/jbc.M301158200. PMID 12642576. Unknown parameter |month= ignored (help)
  5. Tempel W, Rabeh WM, Bogan KL; et al. (2007). "Nicotinamide riboside kinase structures reveal new pathways to NAD+". PLoS Biol. 5 (10): e263. PMID 17914902.
  6. Anderson RM, Bitterman KJ, Wood JG; et al. (2002). "Manipulation of a nuclear NAD+ salvage pathway delays aging without altering steady-state NAD+ levels". J. Biol. Chem. 277 (21): 18881&ndash, 90. PMID 11884393.
  7. 7.0 7.1 7.2 Schweiger M, Hennig K, Lerner F, Niere M, Hirsch-Kauffmann M, Specht T, Weise C, Oei SL, Ziegler M (2001). "Characterization of recombinant human nicotinamide mononucleotide adenylyl transferase (NMNAT), a nuclear enzyme essential for NAD synthesis". FEBS Lett. 492 (1–2): 95–100. PMID 11248244. Unknown parameter |month= ignored (help)

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