Towards Understanding Mechanisms of Drug Action and Functions of the Body on the Molecular Level. Studies on histamine with L-histidine decarboxylase, a histamine-forming enzyme, as a probe: from purification to gene knockout.

Histamine has been referred to as an anorexic factor that decreases appetite and fat accumulation and affects feeding behavior. Tuberomammillary histaminergic neurons have been implicated in central mediation of peripheral metabolic signals such as leptin, and centrally released histamine inhibits ob gene expression. Here we have characterized the metabolic phenotype of mice that completely lack the ability to produce histamine because of targeted disruption of the key enzyme in histamine biosynthesis (histidine decarboxylase, HDC). Histochemical analyses confirmed the lack of HDC mRNA, histamine immunoreactivity, and histaminergic innervation throughout the brain of gene knockout mouse. Aged histamine-deficient (HDC−/−) mice are characterized by visceral adiposity, increased amount of brown adipose tissue, impaired glucose tolerance, hyperinsulinemia, and hyperleptinemia. Histamine-deficient animals are not hyperphagic but gain more weight and are calorically more efficient than wild-type controls. These metabolic changes presumably are due to the impaired regulatory loop between leptin and hypothalamic histamine that results in orexigenic dominance through decreased energy expenditure, attenuated ability to induce uncoupling protein-1 mRNA in the brown adipose tissue and defect in mobilizing energy stores. Our results further support the role of histamine in regulation of energy homeostasis.

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Structural basis for the histamine synthesis by human histidine decarboxylase

Acta Crystallographica Section A Foundations and Advances ◽

10.1107/s2053273314095412 ◽

2014 ◽

Vol 70 (a1) ◽

pp. C458-C458

Author(s):

Hirofumi Komori ◽

Yoko Nitta ◽

Hiroshi Ueno ◽

Yoshiki Higuchi

Keyword(s):

Amino Acid ◽

Substrate Specificity ◽

Histidine Decarboxylase ◽

The Body ◽

Structural Basis ◽

Acid Decarboxylase ◽

Amino Acid Decarboxylase ◽

Histamine Production ◽

Novel Drugs ◽

High Sequence Homology

Histamine is a bioactive amine responsible for a variety of physiological reactions, including allergy, gastric acid secretion, and neurotransmission. In mammals, histamine production from histidine is catalyzed by histidine decarboxylase (HDC). Mammalian HDC is a pyridoxal 5'-phosphate (PLP)-dependent decarboxylase and belongs to the same family as mammalian glutamate decarboxylase (GAD) and mammalian aromatic L-amino acid decarboxylase (AroDC). The decarboxylases of this family function as homodimers and catalyze the formation of physiologically important amines like GABA and dopamine via decarboxylation of glutamate and DOPA, respectively. Despite high sequence homology, both AroDC and HDC react with different substrates. For example, AroDC catalyzes the decarboxylation of several aromatic L-amino acids, but has little activity on histidine. Although such differences are known, the substrate specificity of HDC has not been extensively studied because of the low levels of HDC in the body and the instability of recombinant HDC, even in a well-purified form. However, knowledge about the substrate specificity and decarboxylation mechanism of HDC is valuable from the viewpoint of drug development, as it could help lead to designing of novel drugs to prevent histamine biosynthesis. We have determined the crystal structure of human HDC in complex with inhibitors, histidine methyl ester (HME) and alpha-fluoromethyl histidine (FMH). These structures showed the detailed features of the PLP-inhibitor adduct (external aldimine) in the active site of HDC. These data provided insight into the molecular basis for substrate recognition among the PLP-dependent L-amino acid decarboxylases.

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Nanotechnology: A Big Revolution from the Small World

Urologia Journal ◽

10.5301/ru.2013.10620 ◽

2013 ◽

Vol 80 (1) ◽

pp. 46-55 ◽

Cited By ~ 1

Author(s):

Matteo Bassi ◽

Irene Santinello ◽

Andrea Bevilacqua ◽

Pierfrancesco Bassi

Keyword(s):

Carbon Nanotubes ◽

Molecular Level ◽

Medical Science ◽

Small World ◽

The Body ◽

Superparamagnetic Nanoparticles ◽

New Materials ◽

Disease Treatment ◽

History Of ◽

Engineering Physics

Nanotechnology is a multidisciplinary field originating from the interaction of several different disciplines, such as engineering, physics, biology and chemistry. New materials and devices effectively interact with the body at molecular level, yielding a brand new range of highly selective and targeted applications designed to maximize the therapeutic efficiency while reducing the side effects. Liposomes, quantum dots, carbon nanotubes and superparamagnetic nanoparticles are among the most assessed nanotechnologies. Meanwhile, other futuristic platforms are paving the way toward a new scientific paradigm, able to deeply change the research path in the medical science. The growth of nanotechnology, driven by the dramatic advances in science and technology, clearly creates new opportunities for the development of the medical science and disease treatment in human health care. Despite the concerns and the on-going studies about their safety, nanotechnology clearly emerges as holding the promise of delivering one of the greatest breakthroughs in the history of medical science.

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New functions of histamine found in histidine decarboxylase gene knockout mice

Biochemical and Biophysical Research Communications ◽

10.1016/s0006-291x(03)00696-x ◽

2003 ◽

Vol 305 (3) ◽

pp. 443-447 ◽

Cited By ~ 52

Author(s):

Hiroshi Ohtsu ◽

Takehiko Watanabe

Keyword(s):

Knockout Mice ◽

Histidine Decarboxylase ◽

Gene Knockout ◽

Gene Knockout Mice

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Drug Action at the Molecular Level

FEBS Letters ◽

10.1016/0014-5793(78)81219-8 ◽

1978 ◽

Vol 91 (2) ◽

pp. 374-375

Author(s):

E. Cundliffe ◽

J.R. Thompson

Keyword(s):

Molecular Level ◽

Drug Action

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Angiotensin II Type 2 Receptor

Hypertension ◽

10.1161/hypertensionaha.120.11941 ◽

2021 ◽

Author(s):

Naureen Fatima ◽

Sanket N. Patel ◽

Tahir Hussain

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Kidney Diseases ◽

Gene Knockout ◽

The Body ◽

Sodium Reabsorption ◽

Ang Ii ◽

Organ Protection ◽

Organ Systems

The renin-angiotensin system is of vital significance not only in the maintenance of blood pressure but also because of its role in the pathophysiology of different organ systems in the body. Of the 2 Ang II (angiotensin II) receptors, the AT 1 R (Ang II type 1 receptor) has been extensively studied for its role in mediating the classical functions of Ang II, including vasoconstriction, stimulation of renal tubular sodium reabsorption, hormonal secretion, cell proliferation, inflammation, and oxidative stress. The other receptor, AT 2 R (Ang II type 2 receptor), is abundantly expressed in both immune and nonimmune cells in fetal tissue. However, its expression is increased under pathological conditions in adult tissues. The role of AT 2 R in counteracting AT 1 R function has been discussed in the past 2 decades. However, with the discovery of the nonpeptide agonist C21, the significance of AT 2 R in various pathologies such as obesity, hypertension, and kidney diseases have been examined. This review focuses on the most recent findings on the beneficial effects of AT 2 R by summarizing both gene knockout studies as well as pharmacological studies, specifically highlighting its importance in blood pressure regulation, obesity/metabolism, organ protection, and relevance in the treatment of coronavirus disease 2019 (COVID-19).

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