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Butyrylcholinesterase: Structure and Physiological Importance [Butirilkolinesteraz: Yapısı Ve Fizyolojik Önemi]

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Butyrylcholinesterase: Structure and Physiological Importance [Butirilkolinesteraz: Yapısı Ve Fizyolojik Önemi] Türk Biyokimya Dergisi [Turkish Journal of Biochemistry - Turk J Biochem] 2003; 28 (2); 54-61. Derleme [Review Article] Yayın tarihi 4 Ekim, 2003 © TurkJBiochem.com [Published online 4 October, 2003] Butyrylcholinesterase: Structure and Physiological Importance [Butirilkolinesteraz: Yapısı ve Fizyolojik Önemi] A. Neşe Çokuğraş(1) ABSTRACT Butyrylcholinesterase is involved three different enzymatic activities in its structure like its sister enzyme, acetylcholinesterase: esterase, aryl acylamidase and pepti- dase (or protease). Whereas the clear role of acetylcholinesterase in cholinergic neurotransmission is well defined, the real physiological function of butyrylcho- linesterase is still unknown. Both enzymes have similar molecular forms with dif- ferent tissue distribution. Esteratic activity of butyrylcholinesterase becomes more important in scavenging of organophosphate and carbamate inhibitors before they reach to acetylcholinesterase; in regulating cholinergic transmission in the absence of acetylcholinesterase and in inactivation of some drugs such as cocaine aspirin, amitriptyline or in activation of others such as bambuterol, heroin. It is suggested that aryl acylamidase activity plays a role in crosstalking between seratonergic and cholinergic neurotransmission systems. In addition, peptidase activity of butyryl- cholinesterase has a function in the development and progression of Alzheimer disease due to cause the production of β-amyloid protein and to help its diffusion to β-amyloid plaques. (1) Hacettepe University, Faculty of Medicine, Department of Biochemistry, 06100 Ankara, Turkey Key Words: Butyrylcholinesterase; esteratic function of; aryl acylamidase function of; peptidase funtion of. Yazışma Adresi [Correspondence Address] ÖZET Hacettepe University, Faculty of Medicine, Butirilkolinesteraz, kardeş enzimi asetilkolinesteraza benzer şekilde yapısında Department of Biochemistry, 06100 Ankara, Turkey üç farklı enzimatik aktivite barındırır: esteraz, aril açilamidaz ve peptidaz (pro- Tel: +90 312 324 5885 teaz) aktiviteleri. Asetilkolinesterazın kolinerjik sinir iletimindeki rolü tamamen Fax: +90 312 310 0588 anlaşılmış olmasına karşın, butirilkolinesterazın gerçek fizyolojik işlevi bugün E-Mail: [email protected] halen bilinememektedir. Her iki enzim farklı doku dağılımları gösteren benzer moleküler formlara sahiptir. Butirilkolinesterazın esteraz aktivitesi, organofosfat ve karbamat yapılı inhibitörlerin asetilkolinesteraza ulaşamadan dolaşımdan temizlen- mesinde, asetilkolinesteraz yoksunluğunda kolinerjik sinir iletiminin kontrolünde ve kokain, aspirin, amitriptilin gibi bazı ilaçların inaktivasyonu veya bambuterol, heroin gibi bazı ilaçların ise aktivasyonunda önem kazanmaktadır. Enzimin aril açilamidaz aktivitesinin ise seratonerjik ve kolinerjik sinir ilemi sistemleri arasında iletişim sağlama işlevi olduğu ileri sürülmektedir. Ek olarak, enzimin peptidaz veya proteaz aktivitesinin Alzheimer hastalığının gelişmesi ve ilerlemesinde işlevi vardır. Butirilkolinesteraz bu hastalıkta β-amyloid proteinin üretimine ve proteinin β-amy- loid plaklara difüzlenmesine neden olmaktadır. Kayıt tarihi 25 Ağustos 2003; kabul tarihi 12 Eylül 2003 Anahtar Kelimeler: Butirilkolinesteraz; esteratik aktivitesi; aril açilamidaz [Received 25 August 2003; accepted 12 September 2003] aktivitesi; peptidaz aktivitesi. http://www.TurkJBiochem.com 54 ISSN 1303-829X (electronic) 0250-4685 (printed) CONTENTS AChE is known to be abundant in brain, muscle and erythrocyte membrane, whereas BChE has higher ABSTRACT activity in liver, intestine, heart, kidney and lung (8,9). ÖZET Many species such as human, horse, mice exhibit high BChE activity in their plasma, while rat has higher AChE 1. INTRODUCTION activity than BChE in its plasma (2,9,10). Serum BChE 2. MOLECULAR FORMS OF CHOLINESTERASES is synthesized in liver and secreted into plasma (2). 3. STRUCTURE AND ACTION MECHANISM OF AChE and BChE share 65% amino acid sequence ESTERATIC ACTIVE CENTER homology and have similar molecular forms and active 4. GENETIC VARIANTS OF BChE center structure despite being products of different 5. FUNCTIONS OF BChE genes on human choromosomes 7(specifically 7q22) and 3(specifically 3q26), respectively (11). The 5.1. As a Detoxification Enzyme main function of AChE is rapid hydrolysis of the 5.1.1 Succinyldicholine (SuCh) neurotransmitter acetylcholine at cholinergic synapses, 5.1.2 Organophosphates (OPs) and Carbamates and it is one of the fastest enzyme known (12). But 5.1.3. Cocaine individuals whose BChE is absent does not correlate with any physiological abnormality. Its importance as 5.1.4. Aspirin a detoxification enzyme is growing interest in recent 5.1.5. Amitriptyline years. BChE is of pharmacological and toxicological 5.1.6. Anticonvulsant Drugs importance, because it hydrolyzes ester-containing drugs 5.2. As Activator Enzyme and scavenges cholinesterase inhibitors including potent organophosphporus nerve agents before they reach their 5.2.1. Bambuterol synaptic targets (13). 5.2.2. Heroin The presented review focusses on function of BChE as a 5.2.3. CPT-11 (Irinotecan) detoxification enyme and the using as a prophylactic and 5.3. As a Diagnostic Marker therapeutic drug against toxicity of some chemicals. 5.4. Non-Classical Functions of BChE 2. MOLECULAR FORMS OF 5.4.1. Cellular Differentiation and Morphogenesis CHOLINESTERASES 5.4.2. Aryl Acylamidase Activity 5.4.3. Peptidase (Proteinase) or Amidase Activity AChE and BChE present a similar amphiphilic or soluble 6. RESULTS molecular forms in tissues and body fluids with different tissue distribution. These homo- and hetero-oligomeric 7. REFERENCES forms are summarized as follows: 1. Type I amphiphilic dimers: Glycophosphatidyl inositol anchored dimers to plasma membranes exit in 1. INTRODUCTION mammalian muscles, erythrocytes and lymphocytes. It is abundant form of AChE. It is only solubilized Animal cholinesterases are widespread enzymes present by detergents and it aggregates in the absence of in cholinergic and noncholinergic tissues as well as detergents. in their plasma and other body fluids (1-3). They are divided into two classes according to differing in their 2. Type II amphiphilic monomers and dimers: subtrate specificity, behaviour in excess substrate Distinguished from Type I due to devoid of glycolipid and susceptibility to inhibitors: acetylcholinesterase anchore and does not aggregate in the absence of or “true cholinesterase” (AChE; acetylcholine detergents. They are solubilized by salt solutions. These acetylhydrolase, E.C. 3.1.1.7) and butyrylcholinesterase forms are abundant in mammalian brains, muscles and (BChE; acylcholine acylhydrolase, E.C. 3.1.1.8). intestine for both cholinesterases. BChE is also known as pseudocholinesterase, non- 3. Hydrophobic-tailed tetramers: Anchored to plasma specific cholinesterase or simply cholinesterase. AChE membranes by a hydrophobic, 20 kDalton length hydrolyzes acetylcholine faster than other cholinesters polypeptid subunit. This form is abundant for AChE in and is much less active on butyrylcholine. On the mammalian central nervous system. contrary, BChE pereferentially acts on butyrylcholine, 4. Collagen-like tailed forms or asymetric forms: This but also hydrolyzes acetylcholine (2,4). The inhibition of form is characterized by the presence of a collagen-like AChE by excess substrate is one of the key features that tail for anchorage to the basal lamina. It is formed by distinguishes it from BChE. BChE exhibits the substrate the triple helical structure of three collagenic subunits activation in excess substrate (5,6). AChE is inhibited Q, each associated with one (A4), two(A8) or three (A12) selectively by 1,5-bis (4-allyldimethylamminopropyl) tetramers of cholinesterases. It is more abundant for pentan-3-on dibromide (BW 284C51), while BChE is AChE than BChE in nervous-muscle junctions. selectively inhibited by 10-[2-diethylaminopropyl]- 5. Soluble tetrameric form (G4): Composed of the phenothiazid (ethopropazine) and isotetra monoisopropyl four identical monomers and stabilized by hydrophobic pyrophopsphate tetramid (iso-OMPA) (7). Their tissue- interactions of hydrophobic amino acids at C terminal specific distribution is also different from each other: of monomers. This form is abundant for BChE in Turk J Biochem, 2003; 28(2); 54-61. 55 Çokuğraş Turk J Biochem, 2003; 28(2); 54-61. 56 Çokuğraş mammalian body fluids and in the soluble fraction of substrate interacts the negatively charged Asp70 and tissue homogenates (14,15). this process triggers the conformational change in the momomer. Then, the two flexible arms of Ω loop come 3. STRUCTURE AND ACTION close to each other and the substrate slides down to MECHANISM OF ESTERATIC Trp82 residue of choline binding site or cation-π site of ACTIVE CENTER the active site. This site was formerly named as anionic site, but now it is known that there is not any residue For many species, monomer is made up approximately with negative charge that is responsible for binding of 574 amino acids and carries a few asparagine-linked quaternary ammonium group. Trp82 also forms cation-π carbohydrate chains. It has also three interchain complex with this group of substrate (6,16,17). disulphide bridges that help to gain specific three Oxyanion hole found near the choline binding site dimentional globular structure of monomer. For includes Gly116, Gly117 and Ala199 and helps to many mammalian species, monomers make dimers rotate the substrate from vertical to horizontal position via disulphide
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