Structural studies of human alkaline phosphatase in complex with strontium: implication for its secondary effect in bones.

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Llinas P, Masella M, Stigbrand T, Menez A, Stura EA, Le Du MH

Structural studies of human alkaline phosphatase in complex with strontium: implication for its secondary effect in bones.

Protein Sci. 2006 Jul;15(7):1691-700.

PubMed ID

16815919 [ View in PubMed

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Abstract

Strontium is used in the treatment of osteoporosis as a ranelate compound, and in the treatment of painful scattered bone metastases as isotope. At very high doses and in certain conditions, it can lead to osteomalacia characterized by impairment of bone mineralization. The osteomalacia symptoms resemble those of hypophosphatasia, a rare inherited disorder associated with mutations in the gene encoding for tissue-nonspecific alkaline phosphatase (TNAP). Human alkaline phosphatases have four metal binding sites--two for zinc, one for magnesium, and one for calcium ion--that can be substituted by strontium. Here we present the crystal structure of strontium-substituted human placental alkaline phosphatase (PLAP), a related isozyme of TNAP, in which such replacement can have important physiological implications. The structure shows that strontium substitutes the calcium ion with concomitant modification of the metal coordination. The use of the flexible and polarizable force-field TCPEp (topological and classical polarization effects for proteins) predicts that calcium or strontium has similar interaction energies at the calcium-binding site of PLAP. Since calcium helps stabilize a large area that includes loops 210-228 and 250-297, its substitution by strontium could affect the stability of this region. Energy calculations suggest that only at high doses of strontium, comparable to those found for calcium, can strontium substitute for calcium. Since osteomalacia is observed after ingestion of high doses of strontium, alkaline phosphatase is likely to be one of the targets of strontium, and thus this enzyme might be involved in this disease.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Calcium	Alkaline phosphatase, placental type	Protein	Humans	Unknown	Not Available	Details

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Strontium chloride Sr-89	Alkaline phosphatase, germ cell type	Protein	Humans	No	Cofactor	Details
Strontium chloride Sr-89	Alkaline phosphatase, tissue-nonspecific isozyme	Protein	Humans	No	Cofactor	Details

Polypeptides

Name	UniProt ID
Alkaline phosphatase, placental type	P05187	Details