Alkaline Phosphatase in Health and Disease

Introduction of Alkaline phosphatases

Alkaline phosphatases (ALPs), identified as plasma membrane-bound glycoproteins, play a crucial role in hydrolyzing various monophosphate esters at a high pH optimum, releasing inorganic phosphate. Present in prokaryotes and higher eukaryotes, ALPs form a diverse family of dimeric enzymes typically located on cell surfaces. Mammalian ALPs are zinc-containing metalloenzymes encoded by a multigene family, with enzymatic activity dependent on three essential metal ions: two Zn²⁺ and one Mg²⁺. These ions also influence the ALP monomer's conformation and regulate subunit interactions.

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The alkaline phosphatase (ALP), a membrane-bound metalloenzyme with multiple isoenzymes, is believed to have evolved from a single ancestral gene. Three tissue-specific ALP genes on chromosome 2q34-37 produce distinct isoenzymes, while the L/B/K ALP gene on chromosome 1 encodes a family of proteins. Tissue-nonspecific alkaline phosphatase (TNSALP), formed by differential glycosylation, exhibits tissue-specific isoforms abundant in hepatic, skeletal, and renal tissue. The L/B/K gene, significantly longer due to extended introns, comprises 12 exons, contrasting with the 11 exons in other genes. The introns in intestinal, placental, and placental-like genes are notably smaller. Sequences at intron boundaries align with eukaryotic gene consensus. Exon 12 contains mRNA processing signals, including a polyadenylation site. This illuminates ALP's genetic diversity, evolutionary history, and structural intricacies.

Isoforms of Alkaline Phosphatase and Their Distribution

Human alkaline phosphatases (ALPs) exhibit tissue-specific forms, namely placental (PLALP), intestinal (IALP), liver/bone/kidney (L/B/K ALP), and germ cell (GCALP). These isozymes, derived from at least three ALP gene loci, are distinguishable by structural, biochemical, and immunologic methods. PLALP, located on chromosome 2, is heat-stable, abundant in the placenta, and polymorphic with up to 18 allelozymes. IALP, mapping to chromosome 2, is partially heat-stable, prominent in intestinal tissue, and displays distinct fetal and adult forms. GCALP, on chromosome 2, is heat-stable, found in germ cells and some tissues, and can be reexpressed by cancer cells. L/B/K ALP, representing the tissue-nonspecific form, is expressed widely, especially in hepatic, skeletal, and renal tissue. It is encoded by a single genetic locus on chromosome 1.

Fig. 1 AA ribbon diagram of L/B/K ALP protein structure (http://biochem.dental.upenn.edu/).

Alkaline Phosphatase in Diseases

The diagnostic significance of liver and bone alkaline phosphatase activity in serum is well-established. In healthy individuals, bone alkaline phosphatase contributes roughly half of the total alkaline phosphatase activity in adults. The normal serum range for alkaline phosphatase is 20 to 140 U/L. Elevated levels are associated with bone, liver, and other diseases, indicating potential issues like bile duct obstruction, active bone formation, or conditions affecting calcium levels and liver function. Lowered levels are less common and may result from various conditions such as hypophosphatasia, postmenopausal women on estrogen therapy, malnutrition, magnesium deficiency, hypothyroidism, anemia, and certain genetic disorders. Deficiency in TNSALP leads to hypophosphatasia, a metabolic disorder characterized by skeletal abnormalities and dental problems. TNSALP, associated with various diseases, exhibits altered expression in cancer tissues, suggesting its potential role in tumorigenesis. Recent studies propose a novel connection between TNSALP and the toxic effects of extracellular tau protein in Alzheimer's disease, indicating a broader role for alkaline phosphatase in cellular events and diseases.

In conclusion, the intricate structure and diverse isoforms of alkaline phosphatases (ALPs) underscore their crucial role in health and disease. From their evolutionary origins to tissue-specific distribution and diagnostic significance, ALPs play a multifaceted role in various physiological and pathological processes. Understanding the complexities of ALPs contributes to advancements in disease diagnosis and potential therapeutic interventions, shedding light on the dynamic interplay between these enzymes and human health.

References

1. Lowe D., et al. Alkaline phosphatase. StatPearls. 2023.
2. Sharma U., et al. Alkaline phosphatase: an overview. Indian Journal of Clinical Biochemistry. 2014, 29: 269-278.