Poster | Encontro de Jovens Investigadores em Biologia Computacional Estrutural

Instituto Pedro Nunes, Coimbra

2015, 18th December

Poster: “Computational studies addressed to the catalytic mechanism of Histidine Decarboxylase”

Henrique S. Fernandes (1), Nuno M. F. S. A. Cerqueira (1)

(1) UCIBIO/REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre s/n, 4169-007 Porto, PT

Mammalian histidine decarboxylase (mHDC) is an enzyme that requires pyridoxal-5′-phosphate (PLP) as a cofactor [1]. mHDC belongs to the group II of PLP-dependent decarboxylases together with L-DOPA and glutamate decarboxylases, and catalyses the L-histidine decarboxylation from which results histamine.

Histamine plays a key role in several biological events such as immune response, gastric system modulation and as a neurotransmitter in the nervous system. Several inhibitors for histamine action have been studied in order to treat some diseases such as atopic dermatitis, allergies, and cancer.

mHDC has been studied for a long time, but only in 2012 Komori’s [2] group was able to determine X-ray structure of the enzyme and revealed the active site environment. Until date, only hypothesis about the mechanism of mHDC were available and based on homology models (that propose a different active site configuration).

In this work we are studying the catalytic mechanism of mHDC by computational means using the recent X-ray structure of mHDC and a QM/MM methodology.

The results have shown that mHDC catalyses the reaction in a two-step type of mechanism. The first step involves a decarboxylation that is followed by the formation of a carbanion. In the second step, the carbanion is protonated by a base from which results histamine. Our early results indicate that the first step is the limiting reaction step and the full reaction is endothermic by approximately 25 kcal/mol.

[1] Ngo HP, Cerqueira NMFSA, Kim JK, Hong MK, Fernandes PA, et al. 2014. Acta Crystallogr D Biol Crystallogr 70: 596-606;
[2] Komori H, Nitta Y, Ueno H, Higuchi Y. 2012. Acta Crystallogr Sect F Struct Biol Cryst Commun 68: 675-7

Abstracts’ Book | Web Page

Amino Acid Deprivation Using Enzymes as a Targeted Therapy for Cancer and Viral Infections

Pages 283-297 | Received 29 Jul 2016, Accepted 25 Oct 2016, Accepted author version posted online: 04 Nov 2016, Published online: 15 Nov 2016

Introduction: Amino acid depletion in the blood serum is currently being exploited and explored for therapies in tumors or viral infections that are auxotrophic for a certain amino acid or have a metabolic defect and cannot produce it. The success of these treatments is because normal cells remain unaltered since they are less demanding and/or can synthesize these compounds in sufficient amounts for their needs by other mechanisms.

Areas covered: This review is focused on amino acid depriving enzymes and their formulations that have been successfully used in the treatment of several types of cancer and viral infections. Particular attention will be given to the enzymes L-asparaginase, L-arginase, L-arginine deiminase, and L-methionine-γ-lyase.

Expert opinion: The immunogenicity and other toxic effects are perhaps the major limitations of these therapies, but they have been successfully decreased either through the expression of these enzymes from other organisms, recombination processes, pegylation of the selected enzymes or by specific mutations in the proteins. In 2006, FDA has already approved the use of L-asparaginase in the treatment of acute lymphoblastic leukemia. Other enzymes and in particular L-arginase, L-arginine deiminase, and L-methioninase have been showing promising results in vitro and in vivo studies.


oniomANALYSIS is a TCL script that allows an easy way to change the frozen status of each atom in Gaussian Hybrid Systems (ONIOM).

How to use?

Insert follow command in shell:

tclsh oniomFROZEN.tcl [A] [B] [C]


[A] is a flag which defines what type of job is going to be perfomed:

–readfile : residues of file \[C\] will be unfrozen and all others will be frozen

–frozenall : all atoms will be frozen

–unfrozenall : all atoms will be unfrozen

–invert : all previous unfrozen atoms will be frozen and all previous frozen atoms will be unfrozen

–invertnowater : equal to previous but all water molecules \(ResName=WAT\) will be frozen

[B] is the Gaussian 09 input file (.com)

[C] is a file with a list of residues (one number per line) to become unfrozen, frozen all other residues. ONLY works with the –readfile flag.



oniomANALYSIS is a TCL script that allows an easy way to extract data and handling output files from Gaussian 09 calculations.

The script allows get informations about energy about low a high levels in hybrid systems (ONIOM). In this option, scripts generates two files:

  • Energy of all structures
  • Energy of all optimized structures

oniomANALYIS allows also extract the first and last structures and write them in a new input Gaussian files in order to run a following calculation recurring to a previous calculation. In this case two files will be generated:

  • Gaussian input file of first structure
  • Gaussian input file of last structure

Moreover, you could also extract PDB files from Gaussian output files:

  • PDB file with all structures
  • PDB file with all optimized structures
  • PDB file with last structure
  • PDB file with last optimized structure

How to use?

Insert follow command in shell:

tclsh oniomANALYSIS.tcl [A] [B]


[A] is a flag which defines what type of job is going to be perfomed:

–energy : for energy extraction

–gaussian : for Gaussian input files generation

–pdb : for PDB files generation

[B] is the Gaussian 09 output file (.log)