Ser84 of Human Renin Contributes to the Biphasic pH Dependence of the Renin-Angiotensinogen Reaction

Iwata, H; Nakagawa, Tsutomu; Nishiuchi, Kazuhiro; Hiratsuka, Tomoaki; Satou, Ryousuke; Yoshioka, Yuichiro; Fukui, Youko; Suzuki, Fujio; Nakamura, Yukio

doi:10.1271/bbb.60682

Cited by 6 publications

(15 citation statements)

References 26 publications

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“…The concentrations of wild-type and mutant sheep angiotensinogens were determined by complete digestion with excess renin, as described previously. 5) Expression and preparation of recombinant human renins. A stable cell line producing S84G mutant prorenin was established as described above, except that pcDNA3-sAgSP-hPRen-S84G 5) was used as the expression plasmid.…”

Section: Methodsmentioning

confidence: 99%

“…5) Expression and preparation of recombinant human renins. A stable cell line producing S84G mutant prorenin was established as described above, except that pcDNA3-sAgSP-hPRen-S84G 5) was used as the expression plasmid. A stable cell line producing wildtype human prorenin was described previously.…”

Section: Methodsmentioning

confidence: 99%

“…1). The type I pH profile has one major peak at neutral pH with a shoulder at acidic pH, e.g., the reactions of rat renin with rat or sheep angiotensinogen, [3][4][5] and the reaction of mouse renin with mouse angiotensinogen. 6) This type is the most common among renin-angiotensinogen reactions.…”

mentioning

confidence: 99%

“…[7][8][9] The type III profile has two separate peaks at acidic and basic pHs, e.g., the reaction of human renin with sheep angiotensinogen. 5,9) The type IV profile has a typical bell-shape at acidic pH. Very few reports describe this type of pH profile for the renin-angiotensinogen reaction.…”

mentioning

confidence: 99%

“…5) However, the possible contribution of His13 of sheep angiotensinogen and the role of Ser84 of human renin with respect to enzyme kinetics in pH dependence has not yet been determined.…”

mentioning

confidence: 99%

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The Coexistence of Ser84 in Renin and His13 in Angiotensinogen Brings a pH Profile of Two Separate Peaks to the Reaction of Human Renin and Sheep Angiotensinogen

Iwata

Nakagawa

Yoshioka

et al. 2008

Bioscience, Biotechnology, and Biochemistry

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

“…5) However, the possible contribution of His13 of sheep angiotensinogen and the role of Ser84 of human renin with respect to enzyme kinetics in pH dependence has not yet been determined.…”

mentioning

confidence: 99%

See 3 more Smart Citations

The Coexistence of Ser84 in Renin and His13 in Angiotensinogen Brings a pH Profile of Two Separate Peaks to the Reaction of Human Renin and Sheep Angiotensinogen

Iwata

Nakagawa

Yoshioka

et al. 2008

Bioscience, Biotechnology, and Biochemistry

Self Cite

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Comparative bioinformatic and structural analyses of pepsin and renin

Grahame

Dupuis

Bryksa

et al. 2020

Enzyme and Microbial Technology

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Exploring the pH-Dependent Structure–Dynamics–Function Relationship of Human Renin

Henderson

Shen

2020

J. Chem. Inf. Model.

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Renin is a pepsin-like aspartyl protease and an important drug target for the treatment of hypertension; despite three decades' research, its pH-dependent structure-function relationship remains poorly understood. Here we employed the continuous constant pH molecular dynamics (CpHMD) simulations to decipher the acid/base roles of renin's catalytic dyad and the conformational dynamics of the flap, which is a common structural feature among aspartyl proteases. The calculated pK a 's suggest that the catalytic Asp38 and Asp226 serve as the general base and acid, respectively, in agreement with experiment and supporting the hypothesis that renin's neutral optimum pH is due to the substrate-induced pK a shifts of the aspartic dyad. The CpHMD data confirmed our previous hypothesis that hydrogen bond formation is the major determinant of the dyad pK a order. Additionally, our simulations showed that renin's flap remains open regardless of pH, although a Tyr-inhibited state is occasionally formed above pH 5. These findings are discussed in comparison to the related aspartyl proteases, including β-secretases 1 and 2, capthepsin D, and plasmepsin II. Our work represents a first step towards a systematic understanding of the pH-dependent structure-dynamics-function relationships of pepsin-like aspartyl proteases that play important roles in biology and human disease states.Renin-angiotensin-aldosterone system (RAAS) is a critical regulator for blood pressure and systemic vascular resistance. 1,2 As a part of the RAAS system, the aspartic protease renin cleaves a protein called angiotensinogen to generate an inactive decapeptide, angiotensin I, which is further cleaved by the angiotensin converting enzyme (ACE) to produce shorter peptides, including the octapeptide angiotensin II which binds and activates the angiotensin II type 1 (AT 1 ) and type 2 (AT 2 ) receptors. The primary effects of AT 1 receptor activation include vasoconstriction and stimulation of aldosterone synthesis and release with subsequent sodium and fluid retention, which tend to elevate blood pressure. 1 Because of its essential role in the function of RAAS and the high specificity for its only known substrate angiotensinogen, renin is an attractive drug target for the treatment of hypertension. Despite

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Ser84 of Human Renin Contributes to the Biphasic pH Dependence of the Renin-Angiotensinogen Reaction

Cited by 6 publications

References 26 publications

The Coexistence of Ser84 in Renin and His13 in Angiotensinogen Brings a pH Profile of Two Separate Peaks to the Reaction of Human Renin and Sheep Angiotensinogen

The Coexistence of Ser84 in Renin and His13 in Angiotensinogen Brings a pH Profile of Two Separate Peaks to the Reaction of Human Renin and Sheep Angiotensinogen

Comparative bioinformatic and structural analyses of pepsin and renin

Exploring the pH-Dependent Structure–Dynamics–Function Relationship of Human Renin

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