CellcCMP and cUMP participate in the process of bacteria resisting phages

Written | My girlfriend, the old Red Riding Hood, Cyclic nucleotide monophosphates are an important type of second messenger, which is responsible for signal transmission in the body
.

Cyclic adenosine monophosphate (Cyclic adenosine monophosphate, referred to as cAMP) is the most widely distributed and the most in-depth research
.

In bacteria, cAMP signal can regulate gene expression and is an important factor that determines bacterial development and metabolism [1,2]
.

In eukaryotic cells, cAMP can activate protein kinase signaling pathways, thereby initiating responses to external stimuli
.

Cyclic guanosine monophosphate (cGMP) can regulate the relaxation of smooth muscle tissue [3, 4]
.

However, research on cyclic monophosphate pyrimidines, namely cytosine monophosphate (cCMP) and cyclic uridine monophosphate (cUMP), has stalled [5,6]
.

The academic community has determined the existence of cCMP and cUMP in a variety of animal cells through mass spectrometry and other means, and predicted that they are likely to participate in cell development and apoptosis [7], but their specific functions and mechanisms of action are still inconclusive
.

Recently, the Rotem Sorek research group from the Weizmann Institute in Israel and the Philip J.
Kranzusch research group from Harvard Medical School in the United States jointly published a research article titled Cyclic CMP and cyclic UMP mediate bacterial immunity against phages in Cell.
The specific structure of pyrimidine cyclase that synthesizes cyclic monophosphate cCMP and cUMP is analyzed, and it is determined that in bacteria, cyclic monophosphate pyrimidine cCMP and cUMP can act as second messengers to activate their antiviral immune pathways
.

First, the author analyzed nearly 40,000 groups of microbial genomes, and confirmed by cloning the cyclase gene in E.
coli that cyclase can participate in the process of bacteria resisting phage; and the active domain of cyclase is mutated , The function of resisting phage is basically lacking
.

Cyclase is a necessary condition for the formation of several cyclic monophosphate nucleosides.
Therefore, the author next investigates which type or types of nucleoside monophosphates are involved in the process of resisting phage
.

The author discovered that cyclase can effectively catalyze the synthesis of cCMP through radioisotope labeling of raw materials for the formation of nucleoside monophosphates such as GTP, CTP and UTP
.

Therefore, the authors call this pyrimidine cyclase system for antiphage resistance (pyrimidine cyclase system for antiphage resistance) the system that catalyzes the synthesis of cCMP to resist phage, and determined that the gene containing the active domain of pyrimidine cyclase is called pycC
.

Next, the author analyzed and studied 967 pycC genes from bacteria, which can be divided into several groups according to their evolution
.

It is very interesting to find that the AD group of genes can synthesize cUMP and can also resist phage invasion
.

In order to further study the mechanism of pyrimidine cyclase, the author selected group B pyrimidine cyclase (BcPycC) and determined its crystal structure
.

Through the crystal structure, the author determined that BcPycC is a symmetric homodimer, and the β sheet with the specific domain as the center is wrapped with 3 sets of α helices
.

Subsequently, the author conducted an in-depth analysis of this structure and found that aspartic acid residues D52 and D96 are involved in the formation of divalent metal ion channels; N172 asparagine can directly interact with ribose ester oxygen
.

These are the structural basis for pycC to catalyze the synthesis of cCMP and cUMP from CTP and UTP
.

Finally, the author studies how cCMP and cUMP are involved in fighting phage infections
.

The author found that under normal circumstances, about 2% (MOI=0.
02) of cells infected with phage, the bacteria will lyse and die; while the bacteria transferred to the Pycscar system are still alive
.

In the case of MOI=2, the growth of bacteria transferred to the Pycscar system enters a stagnant state
.

In order to determine that this phenomenon is related to cCMP, the author added a high concentration of cCMP to the culture medium.
The normal bacteria did not change much, while the growth of the bacteria transferred to the Pycscar system stopped
.

In summary, the authors found that cCMP and cUMP can be used as second messengers to participate in the process of bacteria resisting phage invasion
.

The authors studied a series of pyrimidine cyclases that can catalyze the synthesis of cCMP and cUMP after phage invasion, and determined that these molecules can initiate antiviral responses
.

Next, the author predicted its functional domain and catalytic site by analyzing the crystal structure of pyrimidine cyclase, and named this system Pycscar
.

This work strongly confirmed the function of cyclic monophosphate pyrimidines to resist phage invasion
.

Original link: https://doi.
org/10.
1016/j.
cell.
2021.
09.
031 Platemaker: Eleven References 1.
Green, J.
, Stapleton, MR, Smith, LJ, Artymiuk, PJ, Kahramanoglou, C.
, Hunt, DM, and Buxton, RS (2014).
Cyclic-AMP and bacterial cyclic-AMP re-ceptor proteins revisited: adaptation for different ecological niches.
Curr.
Opin.
Microbiol.
18, 1–7.
2.
Pastan, I.
, and Perlman, R.
(1970).
Cyclic adenosine monophosphate in bacte- ria.
Science 169, 339–344.
3.
Lincoln, TM (1989).
Cyclic GMP and mechanisms of vasodilation.
Pharmacol.
Ther.
41, 479–502.
4.
Stryer, L.
(1986).
Cyclic GMP cascade of vision.
Annu.
Rev.
Neurosci.
9, 87–119.
5.
Gaion, RM, and Krishna, G.
(1979).
Cytidylate cyclase: the product isolated by the method of Cech and Ignarro is not cytidine 30,50-monophosphate.
Bio- chem.
Biophys.
Res.
Commun.
86, 105–1116.
Seifert, R.
(2015).
cCMP and cUMP:emerging second messengers.
Trends Biochem.
Sci.
40, 8–15.
7.
Seifert, R.
(2017).
cCMP and cUMP across the tree of life: From cCMP and cUMP generators to cCMP- and cUMP-regulated cell functions.
In Handbook of Experimental Pharmacology (Springer), pp.
3–23.
Reprinting instructions [Original Articles] BioArt original articles, personal reposting and sharing are welcome, reprinting is prohibited without permission, the copyrights of all published works are owned by BioArt
.

BioArt reserves all statutory rights and offenders must be investigated
.