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Exogenous and Endogenous Alkaline Phosphatase in Health and Disease

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Enzymology".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 22775

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Special Issue Editors

Prof. Dr. Jan Bilski

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Department of Biomechanics and Kinesiology, Faculty of Health Sciences, Jagiellonian University Medical College, 31-008 Cracow, Poland
Interests: inflammatory bowel diseases; colitis; intestinal permeability; leaky gut; intestinal alkaline phosphatase; physical exercise; muscle fat crosstalk; myokines; adipokines
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Prof. Dr. Tomasz Brzozowski

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Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland
Interests: brain–gut axis; experimental colitis; intestinal permeability; inflammatory bowel diseases; proinflammatory cytokines; adipokines; myokines; lipopolysaccharide; microbiota; obesity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Alkaline phosphatases (APs) are a superfamily of membrane-bound, zinc-containing metalloenzymes that catalyze the hydrolytic removal of phosphate from a wide variety of molecules. The mammalian AP family includes several isozymes, termed tissue-nonspecific APs (TNAPs), which are expressed in bone, liver, and kidneys, and tissue-specific AP, a type of enzyme found in the gut, placenta, and germ cells. TNAP plays an essential role in mineralization of bone in mammals, and TNAP deficiency can lead to hypophosphatasia, a hereditary metabolic defect characterized by severe rickets in children and osteomalacia and dental problems in adults. Overexpression of TNAP in the vasculature was suggested to induce vascular calcification and cardiac hypertrophy.

In recent years, intestinal alkaline phosphatase (IAP) has been of particular interest as a critical factor in maintaining gastrointestinal homeostasis acting by dephosphorylation of other pro-inflammatory mediators, tightening the intestinal mucosal barrier and preventing dysbiosis. Reduced IAP activity may increase the risk of disease through changes in the microbiome, increased intestinal inflammation, and permeability, leading to inflammatory diseases of the gastrointestinal tract. The association of decreased IAP activity with type 2 diabetes, metabolic syndrome, and ischemic heart disease has also been suggested.

AP may be a potentially important therapeutic target in many disorders. For example, the use of specific TNAP inhibitors could prevent vascular calcification and further cardiovascular complications. On the other hand, supplementation with IAP may be a potential therapeutic agent for dysbiosis and intestinal and systemic inflammations often associated with lower gut diseases. Administration of exogenous IAP may also counteract aging-related changes in gastrointestinal function. Furthermore, the human recombinant form of IAP has been developed and has been safely administered to humans without any side effects.

The purpose of this Special Issue is to expand and update our understanding of the role of AP in physiological and pathological processes in our body and AP as a potential target in new therapeutic strategies. Thus, this Special Issue of Biomolecules, entitled “Exogenous and Endogenous Alkaline Phosphatase in Health and Disease”, welcomes the submission of manuscripts either describing original research or reviewing the scientific literature which focuses on this challenging topic.

Prof. Dr. Jan Bilski
Prof. Dr. Tomasz Brzozowski
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

alkaline phosphatase
intestinal alkaline phosphatase
placental alkaline phosphatase
tissue-nonspecific alkaline phosphatase
hypophosphatasia
lipopolysaccharide
inflammation
intestine
intestinal permeability
leaky gut
microbiota
obesity
cardiovascular diseases

Published Papers (6 papers)

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Research

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16 pages, 4695 KiB

Open AccessArticle

Tissue-Nonspecific Alkaline Phosphatase (TNAP) as the Enzyme Involved in the Degradation of Nucleotide Analogues in the Ligand Docking and Molecular Dynamics Approaches

by Rafal Madaj, Bartlomiej Gostynski, Roza Pawlowska and Arkadiusz Chworos

Biomolecules 2021, 11(8), 1104; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11081104 - 27 Jul 2021

Cited by 3 | Viewed by 2116

Abstract

Tissue-nonspecific alkaline phosphatase (TNAP) is known to be involved in the degradation of extracellular ATP via the hydrolysis of pyrophosphate (PPi). We investigated, using three different computational methods, namely molecular docking, thermodynamic integration (TI) and conventional molecular dynamics (MD), whether TNAP may also be involved in the utilization of β,γ-modified ATP analogues. For that, we analyzed the interaction of bisphosphonates with this enzyme and evaluated the obtained structures using in silico studies. Complexes formed between pyrophosphate, hypophosphate, imidodiphosphate, methylenediphosphonic acid monothiopyrophosphate, alendronate, pamidronate and zoledronate with TNAP were generated and analyzed based on ligand docking, molecular dynamics and thermodynamic integration. The obtained results indicate that all selected ligands show high affinity toward this enzyme. The forming complexes are stabilized through hydrogen bonds, electrostatic interactions and van der Waals forces. Short- and middle-term molecular dynamics simulations yielded very similar affinity results and confirmed the stability of the protein and its complexes. The results suggest that certain effectors may have a significant impact on the enzyme, changing its properties. Full article

(This article belongs to the Special Issue Exogenous and Endogenous Alkaline Phosphatase in Health and Disease)

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13 pages, 5052 KiB

Open AccessArticle

Association of Serum Alkaline Phosphatase with the TG/HDL Ratio and TyG Index in Korean Adults

by Da-Hye Son, Hyun-Su Ha and Yong-Jae Lee

Biomolecules 2021, 11(6), 882; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11060882 - 14 Jun 2021

Cited by 6 | Viewed by 2718

Abstract

Alkaline phosphatase (ALP) has long been considered a marker of hepatobiliary and bone disorders, but recent studies have shown that increased ALP activity is correlated with various cardio-metabolic diseases. Thus, we investigated the association of serum ALP level with surrogate markers of insulin resistance such as triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C ratio) and triglyceride and glucose (TyG) index in the general population. The study included 12,868 men and women aged 19 years and older. Participants were categorized into four groups based on serum ALP level (U/L) as follows: Q1: 55–190 U/L, Q2: 191–224 U/L, Q3: 225–265 U/L, and Q4: 266–923 U/L for men, Q1: 48–161 U/L, Q2: 162–198 U/L, Q3: 199–245 U/L, Q4: 246–790 U/L for women. The insulin resistance cut-off levels were defined corresponding to the 75th percentile of the TyG index and TG/HDL-C ratio in the current samples. Odds ratios (ORs) with 95% confidence intervals (CIs) of insulin resistance according to quartile of serum ALP level were calculated using weighted multivariate logistic regression analysis. Compared with Q1, the adjusted OR (95% CI) for insulin resistance of the Q4 serum ALP group was 1.517 (1.234–1.866) in men and 1.881 (1.399–2.528) in women using the TG/HDL-C ratio and 1.374 (1.093–1.728) in men and 2.047 (1.468–2.855) in women using the TyG index after adjusting for confounding variables. Serum ALP levels are independently and positively associated with surrogate markers of insulin resistance in Korean adults. Full article

(This article belongs to the Special Issue Exogenous and Endogenous Alkaline Phosphatase in Health and Disease)

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9 pages, 1122 KiB

Open AccessArticle

Relationship between Serum Alkaline Phosphatase and Low Muscle Mass Index Among Korean Adults: A Nationwide Population-Based Study

by Jun-Hyuk Lee, A-Ra Cho and Yong-Jae Lee

Biomolecules 2021, 11(6), 842; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11060842 - 05 Jun 2021

Cited by 6 | Viewed by 3182

Abstract

Sarcopenia has attracted interest due to its impact on various health problems. Chronic inflammation is an important contributor to sarcopenia. Thus, we aimed to investigate the association between serum alkaline phosphatase (ALP), which is a novel inflammatory marker, and muscle mass. This study included 15,579 adults from the 2008–2011 Korea National Health and Nutrition Survey. Low skeletal muscle mass index (LSMI) was defined as body mass index-adjusted appendicular skeletal muscle mass less than 0.789 for men and 0.512 for women. Multiple logistic regression revealed that the highest ALP tertile was significantly associated with LSMI compared with the lowest ALP tertile in both men [Odds ratio (OR): 1.41; 95% confidence interval (CI): 1.04–1.91] and women (OR: 1.45; 95% CI: 1.00–2.10) after adjusting for other confounders. On the receiver operating characteristic curve analysis, the predictive power was significantly higher for ALP levels than for white blood cell count in women (p < 0.001), whereas the difference was not significant in men (p = 0.515). Our findings suggest the potential use of serum ALP as an inflammatory marker and a predictor of sarcopenia. Full article

(This article belongs to the Special Issue Exogenous and Endogenous Alkaline Phosphatase in Health and Disease)

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12 pages, 1233 KiB

Open AccessArticle

Impact of Venoarterial Extracorporeal Membrane Oxygenation on Alkaline Phosphatase Metabolism after Cardiac Surgery

by Thomas Poschner, Anne-Kristin Schaefer, Doris Hutschala, Georg Goliasch, Julia Riebandt, Klaus Distelmaier, Martin H. Bernardi, Martin Andreas, Ruud Brands, Tandis Aref, Günther Laufer and Dominik Wiedemann

Biomolecules 2021, 11(5), 748; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11050748 - 17 May 2021

Cited by 1 | Viewed by 1929

Abstract

(1) Alkaline phosphatase (AP) is consumed during cardiopulmonary bypass (CPB). A high AP depletion leads to an impaired outcome after cardiac surgery. However, data is scarce on the postoperative course of AP under venoarterial ECMO (VA-ECMO) support. (2) A total of 239 patients with VA-ECMO support between 2000 and 2019 at the Department of Cardiac Surgery (Vienna General Hospital, Austria) were included in this retrospective analysis. Blood samples were collected at several timepoints (baseline, postoperative day (POD) 1–7, POD 14 and 30). Patients were categorized according to the relative AP drop (<60% vs. ≥60%) and ECMO duration (<5 days vs. ≥5 days). (3) Overall, 44.4% reached the baseline AP values within 5 days—this was only the case for 28.6% with a higher AP drop (compared to 62.7% with a lower drop; p = 0.000). A greater AP drop was associated with a significantly higher need for renal replacement therapy (40.9% vs. 61.9%; p = 0.002) and an impaired 1-year survival (51.4% vs. 66.0%; p = 0.031). (4) CPB exceeds the negative impact of VA-ECMO; still, ECMO seems to delay alkaline phosphatase recovery. A greater initial AP drop bears the risk of higher morbidity and mortality. Full article

(This article belongs to the Special Issue Exogenous and Endogenous Alkaline Phosphatase in Health and Disease)

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Review

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12 pages, 649 KiB

Open AccessEditor’s ChoiceReview

Role of Intestinal Alkaline Phosphatase in Innate Immunity

by Sudha B. Singh and Henry C. Lin

Biomolecules 2021, 11(12), 1784; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11121784 - 29 Nov 2021

Cited by 22 | Viewed by 4065

Abstract

Intestinal alkaline phosphatase (IAP) is a multi-functional protein that has been demonstrated to primarily protect the gut. The role of IAP in maintaining intestinal homeostasis is underscored by the observation that IAP expression is defective in many gastrointestinal-related disorders such as inflammatory bowel disease IBD, necrotizing enterocolitis, and metabolic syndrome and that exogenous IAP supplementation improves the outcomes associated with these disorders. Additionally, studies using transgenic IAP-knock out (IAP-KO) mouse models further support the importance of the defensive role of IAP in the intestine. Supplementation of exogenous IAP and cellular overexpression of IAP have also been used in vitro to dissect out the downstream mechanisms of this protein in mammalian cell lines. Some of the innate immune functions of IAP include lipopolysaccharide (LPS) detoxification, protection of gut barrier integrity, regulation of gut microbial communities and its anti-inflammatory roles. A novel function of IAP recently identified is the induction of autophagy. Due to its critical role in the gut physiology and its excellent safety profile, IAP has been used in phase 2a clinical trials for treating conditions such as sepsis-associated acute kidney injury. Many excellent reviews discuss the role of IAP in physiology and pathophysiology and here we extend these to include recent updates on this important host defense protein and discuss its role in innate immunity via its effects on bacteria as well as on host cells. We will also discuss the relationship between IAP and autophagy and how these two pathways may act in concert to protect the gut. Full article

(This article belongs to the Special Issue Exogenous and Endogenous Alkaline Phosphatase in Health and Disease)

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21 pages, 3360 KiB

Open AccessReview

The Physiological and Pathological Role of Tissue Nonspecific Alkaline Phosphatase beyond Mineralization

by Saravanan Sekaran, Selvaraj Vimalraj and Lakshmi Thangavelu

Biomolecules 2021, 11(11), 1564; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11111564 - 21 Oct 2021

Cited by 19 | Viewed by 7337

Abstract

Tissue-nonspecific alkaline phosphatase (TNAP) is a key enzyme responsible for skeletal tissue mineralization. It is involved in the dephosphorylation of various physiological substrates, and has vital physiological functions, including extra-skeletal functions, such as neuronal development, detoxification of lipopolysaccharide (LPS), an anti-inflammatory role, bile pH regulation, and the maintenance of the blood brain barrier (BBB). TNAP is also implicated in ectopic pathological calcification of soft tissues, especially the vasculature. Although it is the crucial enzyme in mineralization of skeletal and dental tissues, it is a logical clinical target to attenuate vascular calcification. Various tools and studies have been developed to inhibit its activity to arrest soft tissue mineralization. However, we should not neglect its other physiological functions prior to therapies targeting TNAP. Therefore, a better understanding into the mechanisms mediated by TNAP is needed for minimizing off targeted effects and aid in the betterment of various pathological scenarios. In this review, we have discussed the mechanism of mineralization and functions of TNAP beyond its primary role of hard tissue mineralization. Full article

(This article belongs to the Special Issue Exogenous and Endogenous Alkaline Phosphatase in Health and Disease)

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