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Physiological Role of Alkaline Phosphatase Explored in Hypophosphatasia

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Physiological Role of Alkaline Phosphatase Explored in Hypophosphatasia Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue: Skeletel Biology and Medicine Physiological role of alkaline phosphatase explored in hypophosphatasia 1 2 Michael P. Whyte • 1 Center for Metabolic Bone Disease and Molecular Research. Shriners Hospital for Children. St. Louis. Missouri, USA. 2Division of Bone and Mineral Diseases, Washington University School of Medicine at Barnes-Jewish Hospital, St. l.ouis, Missouri, USA Address for correspondence: Micnael P Whyte, M.D .. Shriners Hospital for Children, 2001 South Lindbergh Blvd. St. Louis. MO [email protected] Hypophosphatasia (HPP) is the instructive rickets or osteomalacia caused by loss-of-function mutation(s) within TNSALP, the gene that encodes the "tissue nonspecific" isoenzyme of alkaline phosphatase (TNSALP). HPP reveals a critical role for this enzyme in skeletal mineraliution. Increased extracellular levels of pyrido.xal 5' -phosphate and inorganic pyrophosphate (PP;) demonstrate that TNSALP is a phosphomonoester phosphohydrolase and a pyrophosphatase that hydrolyzes much lower concentrations of natural substrates than the artificial substrates of laboratory assays. Clearly, TNSALP acts at physiological pH and "alkaline phosphatase" is a misnomer. Aberrations of vitamin B6 metabolism in HPP revealed that TNSALP is an ectoenz.yme. PP; excesses cause chondrocalcinosis and sometimes arthropathy. The skeletal disease is due to PP; inhibition ofhydroxyapatite crystal growth extracellularly so that crystals form within matrix vesicles but fail to enlarge after these structures rupture. Trials of alkaline phosphatase replacement therapy for HPP suggest that TNSALP functions at the level of skeletal tissues. Keywords: ectoenzyme; inorganic pyrophosphate; osteomalacia; rickets; vitamin B6 Soon after Robison's report,1 his hypothesis was Introduction challenged. ALP was abundant in noncalcifying tis­ Alkaline phosphatase (ALP) was discovered in sues (e.g., liver, intestine, placenta), and extracellu­ 1923 by Robert Robison who suggested this en - lar fluid was supersaturated with P;. 3 Instead, other zyme functioned in skeletal mineralization by functions were proposed (see below).~ liberating inorganic phosphate (P;) f~r hydrox­ In the 1960s, electron microscopy rejuvenated yapatite (HA) crystal propagation (Fig. 1). 1 He Robison's hypothesis when the earliest HA crystals found considerable phosphatase activity in the were discovered within "matrix vesicles" (MVs).7 bone and cartilage of growing rats and hypothe­ MV s seem to be"buds of the plasma membrane sized that mineralization followed hydrolysis ofhex­ of chondrocytes and osteoblasts and are rich in osephosphoric esters. ln 1924, Robison and Soames ALP. During "primary" skeletal mineralization, HA demonstrated its peculiar alkaline pH optimum crystals appear and then grow within MVs. After in vitro. 1 Robison recognized, however, that this MVs rupture, "secondary" mineralization proceeds was not physiological and never referred to "alka­ as HA crystals enlarge and deposit into skeletal line phosphatase." He called his discovery "bone matrix. phosphatase." 1 By the 1990s, the postulated roles for ALP were Beginning in the 1930s, significant clinical in­ many,4~ including hydrolysis of Pi esters for the sight came from measuring ALP in serum because non -P; moiety, transferase action for synthesis of hyperphosphatas~mia usually indicates skeletal or P; esters, regulation of P; metabolism, mainte­ hepatobiliary disease. Quantitation of serum ALP nance of steady-state levels of phosphoryl metabo­ may still be the leading enzyme assay. 2 lites, and action as a phosphoprotein phosphatase. doi 10.1111/j.17 49-6632.2010.05387.x 190 Ann. N.Y. Acad. Sci. 1192 (2010) 190-200 <i;; 2010 New York Academy of Sciences. Whyte Hypophosphatasia and alkaline phosphatase is, ALP hydrolyzes an inhibitor of calcification.3~-9 The principal candidate, inorganic pyrophosphate 'The SIGNIFICANCE ()f (PP;), impairs HA crystal growth and can be hy­ drolyzed by ALP.3•4 In fact (see below), plasma and PHOSPHORIC ESTERS urine levels of PPi are increased in hypophosphata­ sia (HPP).10 in METABOLISM Now, Robison's hypothesis is proven; the "tissue nonspecific" isoenzyme of ALP (TNSALP) is es­ By sential for skeletal mineralization. Verification came ROBERT ROBISON, P1t.O., O.Sc., F.R.S. ,,,1.. ..,,1....-,,v ..... ~,.-­ from the discovery and subsequent characterization •"""""""~_,...,...,,,..... ,.,_., ...., 4 __ _ of the inborn error of metabolism, HPP. -6 In 1988, loss-of-function mutation(s) in TNSALP were first documented in HPP. The pathogenesis of the de­ fective skeletal mineralization in HPP involves im­ 4 paired hydrolysis of PPi, ~ representing the second regulator ofmineralization anticipated by Robison. 1 I Ironically, nearly a century after the discovery of (t).,,. ALP, assay methods do not reflect Robison's ap­ 2 11 preciation of this enzyme. • fn both clinical and research laboratories, ALP is measured using non­ physiological alkalinity (e.g., pH 9.2-10.5) and high concentrations (millimolar) of artificial substrates (e.g., p-nitrophenylphosphate).2 Furthermore, bio­ THE NE.W YORK UNIVERSITY PRESS logic specimens are diluted into buffers without Pi, ,..,Ull111''1f()2' iQIIAltt un· • )IJ!iW YOltl: CITY although P; competitively inhibits ALP.2· 11 These M-•DOJII , ..t, ... ,. .. , .. lfl.LNU.O•o•,no 1,·IQVaUrt'lf' ,....... procedures igndre the pH optimum for ALPs being less alkaline for the lower concentrations of physio­ 2 6 logical substrates. • To understand HPP and what it teaches us about Figure 1. Robert Robison's 1932 summary of his re­ ALP, a brief review of ALP genomic structure and markable work concerning the importance of phospho­ protein chemistry is helpful. ric esters in metabolism (New York University Press, New York).1 Genomic structure and protein chemistry of alkaline phosphatase At plasma membranes, ALP perhaps conditioned transport of Pi> calcium, fat, protein, carbohydrates, ALP (orthophosphoric-monoester phosphohydro­ and Na+ /K+. Sequence analyses suggested coupling lase, alkaline optimum, EC 3.1.3. 1) is found ubiq­ to other proteins, including collagen (see below). In uitously in plants and animals.2 In man, four the placenta, ALP bound the Fe receptor of [gG and ALP isoenzymes are encoded by four separate perhaps transcytosed this immunoglobulin. genes.5 Three are expressed in essentially a tissue­ Additional roles also emerged for ALP in skele­ specific distribution and form intestinal, placen­ tal mineralization, including a plasma membrane tal, and germ cell (placental-like) ALP. The fourth transporter for Pi, an extracellular calcium (Ca2+). is in all cells and designated tissue-nonspecific binding protein that stimulates calcium-Pi precipi­ ALP (TNSALP).5 Liver, bone, and kidney are es­ tation and orients mineral deposjtion into osteoid, pecially rich in TNSALP, and the gene mapping a Caz+ /Mgz+ -ATPase, or a phosphoprotein phos­ symbol is ALPL (ALP-liver), although the function phatase that wnditions matrix for ossification. 8 Fur­ of TNSALP in bone, nut in liver, is known (st:t: thermore, certain domains seemed to bind ALP to below). The distinctive physicochemical properties types I, II, and X collagen in cartilage and bone. Nev­ ( e.g., heat stability, electrophoretic mobility) ofliver, ertheless, an early theory gained preeminence; that bone, and kidney ALP are lost with glycosidase A1111. N.Y. AGa<.I St:i, 1192 (2010) 190 200 © 2010 Ntow Yv1k AGa<.l~111y of St:it!IIGl:!S. 191 Hypophosphatasia and alkaline phosphatase Whyte exposure, reflecting "secondary" isoem:ymes (iso­ phosphorylation-dephosphorylation of a serine forms) having an identical polypeptide sequence but residue. Dissociation of the covalently linked P; different posttranslationa( modifications. 5 seems to be the rate-limiting step. In fact, Pi is a 2 11 The TNSALP gene is at the tip of the short arm of potent competitive inhibitor of ALP. • However, chromosome 1 (lp36.l-p34); the other ALP genes P; may also stabilize the enzyme. 16 Catalytic activity are found at the end of the long arm ofchromosome requires Mg2+ as a cofactor.2 2 (2q34--q37).4 TNSALP seems to be the ancestral Uncertainties persist aboutALPbiosynthesis. The gene.4 human ALPs have a short signal sequence of 17-21 TNSALP exceeds 50 kb and contains 12 exons; 11 amino acid residues and a hydrophobic domain at are translated to form the 507-amin~ acid residue the carboxyterminus. 12 They link to plasma mem­ TNSALP. 12 TATA and Spl sequences may be regula­ brane surfaces tethered to the polar head group of tory elements, but basal expression seems to reflect a phosphatidylinositol-glycan moiety18 and can be "housekeeping» promoter effects, whereas differen­ released by phosphatidylinositol-specific phospho­ tial expression in tissues may use a posttranscrip­ lipase.14 However, their precise interactions with tional mechanism.s TNSALP has two promoters phosphatidylinositol may differ. Intracellular degra­ and two corresponding 51 noncoding exons, la and dation can involve proteosomes. 19 lb, resulting in two different mRNAs. Transcription Lipid-free ALP is found in the circulation. Yet the from the upstream promoter (la) is used in os­ mechanism for its release from cell surfaces is un­ teoblasts, whereas the downstream promoter (lb) known. The process could involve a C or D type is used in liver and kidney. 4 The tissue-specific ALP phosphatidase, detergent action, proteolysis, mem­ genes are smaller than TNSALP,
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