scholarly journals Structural basis for the histamine synthesis by human histidine decarboxylase

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.

scholarly journals Structural basis for divergent and convergent evolution of catalytic machineries in plant aromatic amino acid decarboxylase proteins

2020 ◽  
Vol 117 (20) ◽  
pp. 10806-10817 ◽  
Author(s):  
Michael P. Torrens-Spence ◽  
Ying-Chih Chiang ◽  
Tyler Smith ◽  
Maria A. Vicent ◽  
Yi Wang ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Convergent Evolution ◽  
Structural Features ◽  
Divergent Evolution ◽  
Structural Basis ◽  
Acid Decarboxylase ◽  
Substrate Selectivity ◽  
Amino Acid Decarboxylase ◽  
Catalytic Mechanisms

Radiation of the plant pyridoxal 5′-phosphate (PLP)-dependent aromatic l-amino acid decarboxylase (AAAD) family has yielded an array of paralogous enzymes exhibiting divergent substrate preferences and catalytic mechanisms. Plant AAADs catalyze either the decarboxylation or decarboxylation-dependent oxidative deamination of aromatic l-amino acids to produce aromatic monoamines or aromatic acetaldehydes, respectively. These compounds serve as key precursors for the biosynthesis of several important classes of plant natural products, including indole alkaloids, benzylisoquinoline alkaloids, hydroxycinnamic acid amides, phenylacetaldehyde-derived floral volatiles, and tyrosol derivatives. Here, we present the crystal structures of four functionally distinct plant AAAD paralogs. Through structural and functional analyses, we identify variable structural features of the substrate-binding pocket that underlie the divergent evolution of substrate selectivity toward indole, phenyl, or hydroxyphenyl amino acids in plant AAADs. Moreover, we describe two mechanistic classes of independently arising mutations in AAAD paralogs leading to the convergent evolution of the derived aldehyde synthase activity. Applying knowledge learned from this study, we successfully engineered a shortened benzylisoquinoline alkaloid pathway to produce (S)-norcoclaurine in yeast. This work highlights the pliability of the AAAD fold that allows change of substrate selectivity and access to alternative catalytic mechanisms with only a few mutations.

Substrate specificity of aromatic-L-amino acid decarboxylase

Life Sciences ◽  
1974 ◽  
Vol 14 (5) ◽  
pp. 899-908 ◽  
Author(s):  
Talmage R. Bosin ◽  
Alan R. Buckpitt ◽  
Roger P. Maickel
Keyword(s):  
Amino Acid ◽  
Substrate Specificity ◽  
Acid Decarboxylase ◽  
Amino Acid Decarboxylase

Structural and functional analogies and differences between histidine decarboxylase and aromatic l-amino acid decarboxylase molecular networks: Biomedical implications

2016 ◽  
Vol 114 ◽  
pp. 90-102 ◽  
Author(s):  
Francisca Sanchez-Jiménez ◽  
Almudena Pino-Ángeles ◽  
Rocio Rodríguez-López ◽  
María Morales ◽  
José Luis Urdiales
Keyword(s):  
Amino Acid ◽  
Histidine Decarboxylase ◽  
Molecular Networks ◽  
Acid Decarboxylase ◽  
Amino Acid Decarboxylase

scholarly journals Structural basis for divergent and convergent evolution of catalytic machineries in plant aromatic amino acid decarboxylase proteins

2018 ◽  
Author(s):  
Michael P. Torrens-Spence ◽  
Ying-Chih Chiang ◽  
Tyler Smith ◽  
Maria A. Vicent ◽  
Yi Wang ◽  
...  
Keyword(s):  
Amino Acids ◽  
Natural Products ◽  
Amino Acid ◽  
Aromatic Amino Acid ◽  
Convergent Evolution ◽  
Structural Basis ◽  
Acid Decarboxylase ◽  
Substrate Selectivity ◽  
Amino Acid Decarboxylase ◽  
Catalytic Mechanisms

AbstractRadiation of the plant pyridoxal 5’-phosphate (PLP)-dependent aromatic L-amino acid decarboxylase (AAAD) family has yielded an array of paralogous enzymes exhibiting divergent substrate preferences and catalytic mechanisms. Plant AAADs catalyze either the decarboxylation or decarboxylation-dependent oxidative deamination of aromatic L-amino acids to produce aromatic monoamines or aromatic acetaldehydes, respectively. These compounds serve as key precursors for the biosynthesis of several important classes of plant natural products, including indole alkaloids, benzylisoquinoline alkaloids, hydroxycinnamic acid amides, phenylacetaldehyde-derived floral volatiles, and tyrosol derivatives. Here, we present the crystal structures of four functionally distinct plant AAAD paralogs. Through structural and functional analyses, we identify variable structural features of the substrate-binding pocket that underlie the divergent evolution of substrate selectivity toward indole, phenyl, or hydroxyphenyl amino acids in plant AAADs. Moreover, we describe two mechanistic classes of independently arising mutations in AAAD paralogs leading to the convergent evolution of the derived aldehyde synthase activity. Applying knowledge learned from this study, we successfully engineered a shortened benzylisoquinoline alkaloid pathway to produce (S)-norcoclaurine in yeast. This work highlights the pliability of the AAAD fold that allows change of substrate selectivity and access to alternative catalytic mechanisms with only a few mutations.SignificancePlants biosynthesize their own proteinogenic aromatic L-amino acids, namely L-phenylalanine, L-tyrosine and L-tryptophan, not only for building proteins but also for the production of a plethora of aromatic-amino-acid-derived natural products. Pyridoxal 5’-phosphate (PLP)-dependent aromatic L-amino acid decarboxylase (AAAD) family enzymes play important roles in channeling various aromatic L-amino acids into diverse downstream specialized metabolic pathways. Through comparative structural analysis of four functionally divergent plant AAAD proteins together with biochemical characterization and molecular dynamics simulations, we reveal the structural and mechanistic basis for the rich divergent and convergent evolutionary development within the plant AAAD family. Knowledge learned from this study aids our ability to engineer high-value aromatic-L-amino-acid-derived natural product biosynthesis in heterologous chassis organisms.

scholarly journals Aromatic L-amino Acid Decarboxylase (AADC) deficiency: results from an Italian modified Delphi consensus

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Carlo Fusco ◽  
◽  
Vincenzo Leuzzi ◽  
Pasquale Striano ◽  
Roberta Battini ◽  
...  
Keyword(s):  
Amino Acid ◽  
Diagnostic Delay ◽  
Steering Committee ◽  
Outcome Data ◽  
Diagnosis And Treatment ◽  
Acid Decarboxylase ◽  
Delphi Consensus ◽  
Amino Acid Decarboxylase ◽  
Modified Delphi ◽  
Number Of Patients

Abstract Background Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare and underdiagnosed neurometabolic disorder resulting in a complex neurological and non-neurological phenotype, posing diagnostic challenges resulting in diagnostic delay. Due to the low number of patients, gathering high-quality scientific evidence on diagnosis and treatment is difficult. Additionally, based on the estimated prevalence, the number of undiagnosed patients is likely to be high. Methods Italian experts in AADC deficiency formed a steering committee to engage clinicians in a modified Delphi consensus to promote discussion, and support research, dissemination and awareness on this disorder. Five experts in the field elaborated six main topics, each subdivided into 4 statements and invited 13 clinicians to give their anonymous feedback. Results 100% of the statements were answered and a consensus was reached at the first round. This enabled the steering committee to acknowledge high rates of agreement between experts on clinical presentation, phenotypes, diagnostic work-up and treatment strategies. A research gap was identified in the lack of standardized cognitive and motor outcome data. The need for setting up an Italian working group and a patients’ association, together with the dissemination of knowledge inside and outside scientific societies in multiple medical disciplines were recognized as critical lines of intervention. Conclusions The panel expressed consensus with high rates of agreement on a series of statements paving the way to disseminate clear messages concerning disease presentation, diagnosis and treatment and strategic interventions to disseminate knowledge at different levels. Future lines of research were also identified.

Changes in serotonin contents in brain affect metabolic heat production of rabbits in cold

1978 ◽  
Vol 235 (1) ◽  
pp. R41-R47
Author(s):  
M. T. Lin ◽  
I. H. Pang ◽  
S. I. Chern ◽  
W. Y. Chia
Keyword(s):  
Blood Flow ◽  
Amino Acid ◽  
Heat Loss ◽  
Acid Decarboxylase ◽  
Evaporative Heat Loss ◽  
Decarboxylase Inhibitor ◽  
Ambient Temperatures ◽  
Amino Acid Decarboxylase ◽  
Metabolic Heat ◽  
Normal Limits

Elevating serotonin (5-HT) contents in brain with 5-hydroxytryptophan (5-HTP) reduced rectal temperature (Tre) in rabbits after peripheral decarboxylase inhibition with the aromatic-L-amino-acid decarboxylase inhibitor R04-4602 at two ambient temperatures (Ta), 2 and 22 degrees C. The hypothermia was brought about by both an increase in respiratory evaporative heat loss (Eres) and a decrease in metabolic rate (MR) in the cold. At a Ta of 22 degrees C, the hypothermia was achieved solely due to an increase in heat loss. Depleting brain contents of 5-HT with intraventricular, 5,7-dihydroxytryptamine (5,7-DHT) produced an increased Eres and ear blood flow even at Ta of 2 degrees C. Also, MR increased at all but the Ta of 32 degrees C. However, depleting the central and peripheral contents of 5-HT with p-chlorophenylalanine (pCPA) produced lower MR accompanied by lower Eres in the cold compared to the untreated control. Both groups of pCPA-treated and 5,7-DHT-treated animals maintained their Tre within normal limits. The data suggest that changes in 5-HT content in brain affects the MR of rabbits in the cold. Elevating brain content of 5-HT tends to depress the MR response to cold, while depleting brain content of 5-HT tends to enhance the MR response to cold.

Sign in / Sign up

Export Citation Format

Share Document