Carbonic anhydrase

The carbonic anhydrases (or carbonate dehydratases) (EC 4.2.1.1 (https://www.enzym

e-database.org/query.php?ec=4.2.1.1) ) form a family of enzymes that catalyze the
interconversion between carbon dioxide and water and the dissociated ions of carbonic
acid (i.e. bicarbonate and hydrogen ions).[1] The active site of most carbonic
anhydrases contains a zinc ion. They are therefore classified as metalloenzymes. The
enzyme maintains acid-base balance and helps transport carbon dioxide.[2]
 Carbonic anhydrase

Human carbonic anhydrase II with bound

zinc and carbon dioxide. PDB: 6LUX (http
s://www.rcsb.org/structure/6LUX) ​

Identifiers

EC no. 4.2.1.1 (https://ww

w.enzyme-databas
e.org/query.php?ec
=4.2.1.1)

CAS no. 9001-03-0 (https://

commonchemistry.
cas.org/detail?cas_
 rn=9001-03-0&title
=)

Databases

IntEnz IntEnz view (https://

www.ebi.ac.uk/inte
nz/query?cmd=Sea
rchEC&ec=4.2.1.1)

BRENDA BRENDA entry (htt

p://www.brenda-en
zymes.org/enzyme.
php?ecno=4.2.1.1)

ExPASy NiceZyme view (htt

ps://enzyme.expas
y.org/EC/4.2.1.1)

KEGG KEGG entry (https://

www.genome.jp/db
 get-bin/www_bge
t?enzyme+4.2.1.1)

MetaCyc metabolic pathway

(https://biocyc.org/
META/substring-se
arch?type=NIL&obj
ect=4.2.1.1)

PRIAM profile (http://priam.

prabi.fr/cgi-bin/PRI
AM_profiles_Curren
tRelease.pl?EC=4.2.
1.1)

PDB structures RCSB PDB (https://

www.rcsb.org/sear
ch?q=rcsb_polymer
_entity.rcsb_ec_line
age.id:4.2.1.1)
PDBe (https://www.
 ebi.ac.uk/pdbe/entr
y/search/index?ec_
number:4.2.1.1)
PDBsum (https://w
ww.ebi.ac.uk/thornt
on-srv/databases/c
gi-bin/enzymes/Get
Page.pl?ec_number
=4.2.1.1)

Gene Ontology AmiGO (http://amig

o.geneontology.or
g/amigo/term/GO:0
004089) /
QuickGO (https://w
ww.ebi.ac.uk/Quick
GO/term/GO:00040
89)
 Search

PMC articles (https://www.

ncbi.nlm.nih.gov/entr
ez/query.fcgi?db=pu
bmed&term=4.2.1.1%
5BEC/RN%20Numbe
r%5D%20AND%20p
ubmed%20pmc%20l
ocal%5Bsb%5D)

PubMed articles (https://www.

ncbi.nlm.nih.gov/entr
ez/query.fcgi?db=pu
bmed&term=4.2.1.1%
5BEC/RN%20Numbe
r%5D)

NCBI proteins (https://ww

w.ncbi.nlm.nih.gov/p
rotein?term=4.2.1.1%
5BEC/RN%20Numbe
r%5D)
Eukaryotic-type carbonic anhydrase

Identifiers

Symbol Carb_anhydrase

Pfam PF00194 (https://w

ww.ebi.ac.uk/interp
ro/entry/pfam/PF00
194)

InterPro IPR001148 (https://

www.ebi.ac.uk/inte
rpro/entry/IPR00114
8)

PROSITE PDOC00146 (http

s://prosite.expasy.o
rg/PDOC00146)

SCOP2 1can (http://scop2.

mrc-lmb.cam.ac.u
k/search?t=txt;q=1c
 an) / SCOPe (http
s://scop.berkeley.e
du/pdb/code=1ca
n) / SUPFAM (htt
p://supfam.org/SUP
ERFAMILY/cgi-bin/
search.cgi?search_
field=1can)

Membranome 333 (http://membra

nome.org/protein_s
uperfamilies/333)
 Available protein structures:

Pfam structures (http://pfa

m.xfam.org/family/P
F00194?tab=pdbBloc
k) / ECOD (http://pro
data.swmed.edu/eco
d/complete/search?k
w=PF00194)

PDB RCSB PDB (https://w

ww.rcsb.org/search?
q=rcsb_polymer_enti
ty_annotation.annota
tion_id:PF00194%20
AND%20rcsb_polym
er_entity_annotation.
type:Pfam) ; PDBe (h
ttps://www.ebi.ac.u
k/pdbe/entry/search/
index?pfam_accessi
on:PF00194) ; PDBj
 (https://pdbj.org/sear
ch/pdb?other_db_sel
ect=PFam&other_db
_field=PF00194)

PDBsum structure summary (h

ttps://www.ebi.ac.u
k/thornton-srv/datab
ases/cgi-bin/pdbsu
m/GetPfamStr.pl?pfa
m_id=PF00194)

Carbonic anhydrase helps maintain acid–base homeostasis, regulate pH, and fluid
balance. Depending on its location, the role of the enzyme changes slightly. For
example, carbonic anhydrase produces acid in the stomach lining. In the kidney, the
control of bicarbonate ions influences the water content of the cell. The control of
bicarbonate ions also influences the water content in the eyes. Inhibitors of carbonic
anhydrase are used to treat glaucoma, the excessive build-up of water in the eyes.
Blocking this enzyme shifts the fluid balance in the eyes to reduce fluid build-up
thereby relieving pressure.[2][3]

Carbonic anhydrase is critical to hemoglobin function via the Bohr effect which
catalyzes the hydration of carbon dioxide to form carbonic acid and rapidly dissociate
into water.[4] Essentially an increase in carbon dioxide results in lowered blood pH,
which lowers oxygen-hemoglobin binding.[5] The opposite is true where a decrease in
the concentration of carbon dioxide raises the blood pH which raises the rate of
oxygen-hemoglobin binding. Relating the Bohr effect to carbonic anhydrase is simple:
carbonic anhydrase speeds up the reaction of carbon dioxide reacting with water to
produce hydrogen ions (protons) and bicarbonate ions.

To describe equilibrium in the carbonic anhydrase reaction, Le Chatelier's principle is

used. Most tissue is more acidic than lung tissue because carbon dioxide is produced
by cellular respiration in these tissues, where it reacts with water to produce protons
and bicarbonate. Because the carbon dioxide concentration is higher, the equilibrium
shifts to the right, to the bicarbonate side. The opposite is seen in the lungs, where
carbon dioxide is being released, reducing its concentration, so the equilibrium shifts to
the left, favoring carbon dioxide production.[6]

Occurrence and function

Carbonic anhydrase was initially isolated and characterised from red blood cells in
1933, with simultaneous reports by Meldrum and Roughton (at Cambridge University in
the United Kingdom) and by Stadie and O’Brien (at the University of Pennsylvania in
the United States),[7][8] both while searching for a "catalytic factor... necessary for rapid
transit of the HCO3- [bicarbonate anion] from the erythrocyte to... pulmonary
capillar[ies]".[9]

Regulation of pH
Carbonic anhydrase plays an essential role in regulating the blood pH, which speeds up
the CO2 + H2O HCO3- + H+ reaction to ensure the equilibrium balance is rapidly
maintained. The equilibrium reaction is influenced by the proportion of bicarbonate and
H+ to carbon dioxide.[10] The HCO3- is a conjugate base that neutralizes acids, and the
H+ is a conjugate acid that neutralizes bases by Acid-base homeostasis. The HCO3-
and H+ are ideal for buffering pH in the blood and tissues because the pKa is close to
the physiological pH = 7.2 – 7.6. Since HCO3- and H+ are regulated in the kidneys and
plasma carbon dioxide is regulated in the lungs, both actions in the kidneys and lungs
are important to maintain the stability of blood pH. Therefore, carbonic anhydrase helps
with the H+ secretion into the lumen of the kidney renal tubule and the reabsorption of
HCO3- in the kidneys. Also, it helps the carbon dioxide transport from the lung tissue to
the alveoli in the pulmonary capillary, where the carbon dioxide will be excreted during
exhalation.[10]

Carbonic anhydrase is a very ancient enzyme found in both domains of prokaryotes

that exists in six different classes among most of the living organisms.[11] These families
are not similar in sequence or structure because they evolved independently of each
other, but all evolved the same Zn2+ active site structure, showing a great example of
convergent evolution.

Background
An enzyme is a substance that acts as a catalyst in living organisms which helps to
speed up chemical reactions.[12] Carbonic anhydrase is one important enzyme that is
found in red blood cells, gastric mucosa, pancreatic cells, and even renal tubules. It
was discovered in the year 1932 and it has been categorized into three general
classes.[13] Class one being alpha carbonic anhydrase which is found in mammals,
class two being beta carbonic anhydrase which is found in bacteria and plants and
lastly, class three which is gamma carbonic anhydrase which is found in methanogen
bacteria in hot springs.[14] The three classes of carbonic anhydrase all have the same
active site with a Zn metal centre; however, they are not structurally similar to each
other. The main role of carbonic anhydrase in humans is to catalyze the conversion of
carbon dioxide to carbonic acid and back again. However, it can also help with CO2
transport in the blood which in turn helps respiration. It can even function in the
formation of hydrochloric acid by the stomach.[Citation needed] Therefore, the role of
carbonic anhydrase depends on where it is found in the body.

Structure
In mammalian CA II, the active site consists of the following: a hard Lewis acid Zn+2
metal atom coordinated to His -94, -96, and -119 residues 109˚ apart from one another
and a hydroxide ion (pKa=6.8; 120° in Td configuration, a hydrophobic pocket adjacent
to Zinc-bound hydroxide consisting of by Val-143 at its base and Val-121, Trp-209, and
Leu-198 at its neck, a Proton Shuttling Residue (PSR) His-64 H+ shuttles H+ in and out
of active site via conformational switching, and a hydrogen bonding network consisting
of Thr-199 hydroxyl group and Glu-106 the carboxyl group which stabilizes the Zinc-
bound hydroxide by facilitating the orientation of water molecules in the active side to a
specific geometric configuration. CA II has a turnover frequency of 106 s−1 which is 107
times faster than the uncatalyzed reaction.

Reaction

Schematic of the cyclic reaction mechanism

catalyzed by carbonic anhydrase II.[15]

The reaction that shows the catalyzation of carbonic anhydrase in our tissues is:

CO2 + H2O ⟶ H2CO3 ⟶ H+ + HCO−3

The catalyzation of carbonic anhydrase in the lungs is shown by:

H+ + HCO−3 ⟶ H2CO3 ⟶ CO2 + H2O

The reason for the reactions being in opposite directions for the tissues and lungs is
because of the different pH levels found in them. Without the carbonic anhydrase
catalyst, the reaction is very slow, however with the catalyst the reaction is 107 times
faster.
The reaction catalyzed by carbonic anhydrase is:

−
HCO3 + H+ ⇌ CO2 + H2O
Carbonic acid has a pKa of around 6.36 (the exact value depends on the medium), so at
pH 7 a small percentage of the bicarbonate is protonated.

Carbonic anhydrase is one of the fastest enzymes, and its rate is typically limited by the
diffusion rate of its substrates. Typical catalytic rates of the different forms of this
enzyme ranging between 104 and 106 reactions per second.[15]

The uncatalyzed reverse reaction is relatively slow (kinetics in the 15-second range).
This is why a carbonated drink does not instantly degas when opening the container;
however, it will rapidly degas in the mouth when it comes in contact with carbonic
anhydrase that is contained in saliva.[16]

An anhydrase is defined as an enzyme that catalyzes the removal of a water molecule

from a compound, and so it is this "reverse" reaction that gives carbonic anhydrase its
name, because it removes a water molecule from carbonic acid.

In the lungs carbonic anhydrase converts bicarbonate to carbon dioxide, suited for
exhalation.

CO2 transport

Active site of CAII enzyme (PDB

code: 1CA2) which O = red, N =
blue, Zn = grey and C = green

Carbon dioxide is transported in the blood in three forms:

 1. Dissolved as gas in plasma – 7-
10%
2. Bound to hemoglobin as
carbaminohemoglobin in red
blood cells – 20%
3. Present as bicarbonate ion in
plasma and transported as
bicarbonate - 70%[17]

Mechanism

Close-up rendering of active site of

human carbonic anhydrase II,
showing three histidine residues
and a hydroxide group coordinating
(dashed lines) the zinc ion at
center. From PDB: 1CA2 (https://w
ww.rcsb.org/structure/1CA2) ​.
 CAII enzyme (PDB code: 1CA2)
showing the secondary structures
and the hydrophobic pocket (right
side of the Zn2+) formed by the
beta sheet (blue) and the two valine
and one tryptophan side chains

A zinc prosthetic group in the enzyme is coordinated in three positions by histidine

side-chains. The fourth coordination position is occupied by water. A fourth histidine is
close to the water ligand, facilitating formation of Zn-OH center, which binds CO2 to
give a zinc bicarbonate.[18] The construct is an example of general acid – general base
catalysis (see the article "Acid catalysis"). The active site also features a pocket suited
for carbon dioxide, bringing it close to the hydroxide group. Kinetic studies performed
determine the following mechanism for the enzyme: In Step 1 & 2, the nucleophile O−
on the hydroxide ion coordinated to Zn2+ performs a nucleophilic attack on the partially
electrophilic carbon on the CO2 molecule. Here the Zn2+ acts as a Lewis acid that
lowers the pKa of the coordinated OH2 ligand from ~7-8 down to 6.8 as Td , which
drives the deprotonation of water to a hydroxide ion and the free proton is neutralized
by the surrounding buffer. In step 3), a proton transfer (H+) occurs from the OH−1 to the
non-coordinated O− in CO3−2 coordinated to the Zn+2 atom in the active site. Next, a
bicarbonate ion is released and the catalytic site is regenerated through the binding of
another water molecule in exchange for the bicarbonate ion . In step 4), the
coordinated water ligand is deprotonated facilitated by the Zn+2 to generate another
hydroxide ion to start the cycle over again.[19][20]
Families

Ribbon diagram of human carbonic

anhydrase II. Active site zinc ion
visible at center. From PDB: 1CA2
(https://www.rcsb.org/structure/1C
A2) ​.

At least five distinct CA families are recognized: α, β, γ, δ and ζ. These families have no
significant amino acid sequence similarity and in most cases are thought to be an
example of convergent evolution. The α-CAs are found in humans.

α-CA
Vertebrates, algae, plants, and some bacteria have this family of CAs.

The CA enzymes found in mammals are divided into four broad subgroups, which, in
turn consist of several isoforms:

the cytosolic CAs (CA-I, CA-II, CA-

III, CA-VII and CA XIII) (CA1 (https://
www.genenames.org/data/gene-sy
mbol-report/#!/hgnc_id/1368) , CA2
(https://www.genenames.org/data/
gene-symbol-report/#!/hgnc_id/137
3) , CA3 (https://www.genenames.o
rg/data/gene-symbol-report/#!/hgn
c_id/1374) , CA7 (https://www.gene
names.org/data/gene-symbol-repo
rt/#!/hgnc_id/1381) , CA13 (https://w
ww.genenames.org/data/gene-sym
bol-report/#!/hgnc_id/14914) )
mitochondrial CAs (CA-VA and CA-
VB) (CA5A (https://www.genename
s.org/tools/search/#!/genes?query=
CA5A) , CA5B (https://www.genena
mes.org/tools/search/#!/genes?que
ry=CA5B) )
 secreted CAs (CA-VI) (CA6 (https://
www.genenames.org/data/gene-sy
mbol-report/#!/hgnc_id/1380) )
membrane-associated CAs (CA-IV,
CA-IX, CA-XII, CA-XIV and CA-XV)
(CA4 (https://www.genenames.org/
data/gene-symbol-report/#!/hgnc_i
d/1375) , CA9 (https://www.genena
mes.org/data/gene-symbol-report/
#!/hgnc_id/1383) , CA12 (https://ww
w.genenames.org/data/gene-symb
ol-report/#!/hgnc_id/1371) , CA14 (ht
tps://www.genenames.org/data/ge
ne-symbol-report/#!/hgnc_id/137
2) )
There are three additional "acatalytic" human carbonic anhydrase isoforms (CA-VIII,
CA-X, and CA-XI) (CA8 (https://www.genenames.org/data/gene-symbol-report/#!/hg
nc_id/1382) , CA10 (https://www.genenames.org/data/gene-symbol-report/#!/hgnc_i
d/1369) , CA11 (https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/13
70) ) whose functions remain unclear.[21]

This image shows the ligands and

pocket style of carbonic
anhydrase.[22]
Comparison of mammalian carbonic anhydrases

Molecular Location Specific activity of Sensit

Isoform Gene mass[23] human enzymes,[a][24] sulfonam
[23]
(kDa) Cell Tissue (s−1) KI (nM

CA1
(http
s://w
ww.g
enen
ame
s.or
g/dat red blood
CA-I a/ge 29 cytosol cell and GI 2.0 × 105 250
ne-s tract
ymbo
l-rep
ort/
#!/hg
nc_i
d/136
8)

CA-II CA2 29 cytosol almost 1.4 × 106 12

(http ubiquitous
s://w
ww.g
enen
ame
s.or
g/dat
a/ge
ne-s
ymbo
l-rep
ort/
#!/hg
nc_i
 d/137
3)

CA3
(http
s://w
ww.g
enen
ame
s.or 8% of
g/dat soluble
CA-III a/ge 29 cytosol protein in 1.3 × 104 240000
ne-s Type I
ymbo muscle
l-rep
ort/
#!/hg
nc_i
d/137
4)

CA4
(http
s://w
ww.g
enen
ame
s.or
g/dat GI tract,
extracellular
CA-IV a/ge 35 kidney, 1.1 × 106 74
GPI-linked
ne-s endothelium
ymbo
l-rep
ort/
#!/hg
nc_i
d/137
5)
 CA5A
(http
s://w
ww.g
enen
ame
s.or
34.7
CA-VA g/too mitochondria liver 2.9 × 105 63
(predicted)
ls/se
arch/
#!/ge
nes?
query
=CA5
A)

CA5B
(http
s://w
ww.g
enen
ame
s.or
36.4 widely
CA-VB g/too mitochondria 9.5 × 105 54
(predicted) distributed
ls/se
arch/
#!/ge
nes?
query
=CA5
B)

CA-VI CA6 39–42 secretory saliva and 3.4 × 105 11

(http milk
s://w
ww.g
enen
ame
s.or
g/dat
 a/ge
ne-s
ymbo
l-rep
ort/
#!/hg
nc_i
d/138
0)

CA7
(http
s://w
ww.g
enen
ame
s.or
g/dat
widely
CA-VII a/ge 29 cytosol 9.5 × 105 2.5
distributed
ne-s
ymbo
l-rep
ort/
#!/hg
nc_i
d/138
1)

CA-IX CA9 54, 58 cell normal GI 3.8 × 105 16

(http membrane- tract,
s://w associated several
ww.g cancers
enen
ame
s.or
g/dat
a/ge
ne-s
ymbo
l-rep
 ort/
#!/hg
nc_i
d/138
3)

CA12
(http
s://w
ww.g
enen
ame
s.or
g/dat extracellularily kidney,
CA-XII a/ge 44 located active certain 4.2 × 105 5.7
ne-s site cancers
ymbo
l-rep
ort/
#!/hg
nc_i
d/137
1)

CA- CA13 29 cytosol widely 1.5 × 105 16

XIII[25] (http distributed
s://w
ww.g
enen
ame
s.or
g/dat
a/ge
ne-s
ymbo
l-rep
ort/
#!/hg
nc_i
 d/149
14)

CA14
(http
s://w
ww.g
enen
ame
s.or kidney,
g/dat extracellularily heart,
CA-XIV a/ge 54 located active skeletal 3.1 × 105 41
ne-s site muscle,
ymbo brain
l-rep
ort/
#!/hg
nc_i
d/137
2)

CA15
(http
s://w
ww.g
enen
ame
s.or
g/dat kidney, not
CA- a/ge extracellular expressed
[26]
34–36 4.7 × 105 72
XV ne-s GPI-linked in human
ymbo tissues
l-rep
ort/
#!/hg
nc_i
d/80
73
3)
 a. Except for mouse CA XV.
b. Acetazolamide in this table.

β-CA
Most prokaryotic and plant chloroplast CAs belong to the beta family. Two signature
patterns for this family have been identified:

C-[SA]-D-S-R-[LIVM]-x-[AP]
[EQ]-[YF]-A-[LIVM]-x(2)-[LIVM]-
x(4)-[LIVMF](3)-x-G-H-x(2)-C-G

γ-CA
The gamma class of CAs comes from methanogens, methane-producing archaea that
grow in hot springs.

δ-CA
The delta class of CAs has been described in diatoms. The distinction of this class of CA
has recently[27] come into question, however.
ζ-CA
The zeta class of CAs occurs exclusively in bacteria in a few chemolithotrophs and
marine cyanobacteria that contain cso-carboxysomes.[28] Recent 3-dimensional
analyses[27] suggest that ζ-CA bears some structural resemblance to β-CA, particularly
near the metal ion site. Thus, the two forms may be distantly related, even though the
underlying amino acid sequence has since diverged considerably.

η-CA
The eta family of CAs was recently found in organisms of the genus Plasmodium. These
are a group of enzymes previously thought to belong to the alpha family of CAs,
however it has been demonstrated that η-CAs have unique features, such as their
metal ion coordination pattern.[29]

ι-CA
The iota class is the most recent class of CAs described. It has been discovered in the
marine diatom Thalassiosira pseudonana, and is widespread among marine
phytoplankton.[30] In diatoms, the ι-CA is essential for the CO2-concentrating
mechanisms and - in contrast to other CA classes - it can use manganese instead of
zinc as metal cofactor.[30] Homologs of the ι-CA have been also confirmed in gram-
negative bacteria, where can be present as a protein homodimer.[31]
Structure and function
Several forms of carbonic anhydrase occur in nature. In the best-studied α-carbonic
anhydrase form present in animals, the zinc ion is coordinated by the imidazole rings of
3 histidine residues, His94, His96, and His119.[32]

The primary function of the enzyme in animals is to interconvert carbon dioxide and
bicarbonate to maintain acid-base balance in blood and other tissues, and to help
transport carbon dioxide out of tissues.

There are at least 14 different isoforms in mammals. Plants contain a different form
called β-carbonic anhydrase, which, from an evolutionary standpoint, is a distinct
enzyme, but participates in the same reaction and also uses a zinc ion in its active site.
In plants, carbonic anhydrase helps raise the concentration of CO2 within the
chloroplast in order to increase the carboxylation rate of the enzyme RuBisCO. This is
the reaction that integrates CO2 into organic carbon sugars during photosynthesis, and
can use only the CO2 form of carbon, not carbonic acid or bicarbonate.

Cadmium-containing
carbonic anhydrase
Marine diatoms have been found to express a new form of ζ carbonic anhydrase. T.
weissflogii, a species of phytoplankton common to many marine ecosystems, was
found to contain carbonic anhydrase with a cadmium ion in place of zinc.[33] Previously,
it had been believed that cadmium was a toxic metal with no biological function
whatsoever. However, this species of phytoplankton appears to have adapted to the
low levels of zinc in the ocean by using cadmium when there is not enough zinc.[34]
Although the concentration of cadmium in sea water is also low (about 1x10−16 molar),
there is an environmental advantage to being able to use either metal depending on
which is more available at the time. This type of carbonic anhydrase is therefore
cambialistic, meaning it can interchange the metal in its active site with other metals
(namely, zinc and cadmium).[35]

Similarities to other carbonic

anhydrases
The mechanism of cadmium carbonic anhydrase (CDCA) is essentially the same as that
of other carbonic anhydrases in its conversion of carbon dioxide and water into
bicarbonate and a proton.[36] Additionally, like the other carbonic anhydrases, CDCA
makes the reaction go almost as fast as the diffusion rate of its substrates, and it can
be inhibited by sulfonamide and sulfamate derivatives.[36]

Differences from other carbonic

anhydrases
Unlike most other carbonic anhydrases, the active site metal ion is not bound by three
histidine residues and a hydroxide ion. Instead, it is bound by two cysteine residues,
one histidine residue, and a hydroxide ion, which is characteristic of β-CA.[36][37] Due to
the fact that cadmium is a soft acid, it will be more tightly bound by soft base
ligands.[35] The sulfur atoms on the cysteine residues are soft bases, thus binding the
cadmium more tightly than the nitrogen on histidine residues would. CDCA also has a
three-dimensional folding structure that is unlike any other carbonic anhydrase, and its
amino acid sequence is dissimilar to the other carbonic anhydrases.[36] It is a monomer
with three domains, each one identical in amino acid sequence and each one
containing an active site with a metal ion.[37]

Another key difference between CDCA and the other carbonic anhydrases is that CDCA
has a mechanism for switching out its cadmium ion for a zinc ion in the event that zinc
becomes more available to the phytoplankton than cadmium. The active site of CDCA is
essentially "gated" by a chain of nine amino acids with glycine residues at positions 1
and 9. Normally, this gate remains closed and the cadmium ion is trapped inside.
However, due to the flexibility and position of the glycine residues, this gate can be
opened in order to remove the cadmium ion. A zinc ion can then be put in its place and
the gate will close behind it.[36] As a borderline acid, zinc will not bind as tightly to the
cysteine ligands as cadmium would, but the enzyme will still be active and reasonably
efficient. The metal in the active site can be switched between zinc and cadmium
depending on which one is more abundant at the time. It is the ability of CDCA to utilize
either cadmium or zinc that likely gives T. weissflogii a survival advantage.[34]

Transport of cadmium
Cadmium is still considered lethal to phytoplankton in high amounts. Studies have
shown that T. weissflogii has an initial toxic response to cadmium when exposed to it.
The toxicity of the metal is reduced by the transcription and translation of phytochelatin,
which are proteins that can bind and transport cadmium. Once bound by phytochelatin,
cadmium is no longer toxic, and it can be safely transported to the CDCA enzyme.[33]
It's also been shown that the uptake of cadmium via phytochelatin leads to a significant
increase in CDCA expression.[33]

CDCA-like proteins
Other phytoplankton from different water sources have been tested for the presence of
CDCA. It was found that many of them contain proteins that are homologous to the
CDCA found in T. weissflogii.[33] This includes species from Great Bay, New Jersey as
well as in the Pacific Ocean near the equator. In all species tested, CDCA-like proteins
showed high levels of expression even in high concentrations of zinc and in the
absence of cadmium.[33] The similarity between these proteins and the CDCA
expressed by T. weissflogii varied, but they were always at least 67% similar.[33]
Carbon capture and
sequestration
Carbonic anhydrase could in principle prove relevant to carbon capture. Some carbonic
anhydrases can withstand temperatures up to 107 °C and extreme alkalinity (pH >
10).[38] A pilot run with the more stable CA on a flue stream that consisted of 12–13%
mol composition CO₂ had a capture rate of 63.6% over a 60-hour period with no
noticeable effects in enzyme performance. CA was placed in a N-
methyldiethanolamine (MDEA) solution where it served to increase the concentration
difference (driving force) of CO2 between the flue stream of the power plant and liquid
phase in a liquid-gas contactor.[38]

See also

Carbonic anhydrase inhibitor

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Further reading

Lyall V, Alam RI, Phan DQ, Ereso GL,

Phan TH, Malik SA, et al. (September
2001). "Decrease in rat taste receptor
cell intracellular pH is the proximate
stimulus in sour taste transduction".
American Journal of Physiology. Cell
Physiology. 281 (3): C1005-13.
doi:10.1152/ajpcell.2001.281.3.C1005 (htt
ps://doi.org/10.1152%2Fajpcell.2001.281.
3.C1005) . PMID 11502578 (https://pubm
ed.ncbi.nlm.nih.gov/11502578) .

External links

Overview of all the structural

information available in the PDB for
 UniProt: P00918 (https://www.ebi.a
c.uk/pdbe/pdbe-kb/proteins/P0091
8) (Human Carbonic anhydrase 2)
at the PDBe-KB.
Portal: Biology

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