The enzyme cystathionine γ-lyase (EC 4.4.1.1, CTH or CSE; also cystathionase; systematic name
L-cystathionine cysteine-lyase (deaminating; 2-oxobutanoate-forming)) breaks down
cystathionine
Cystathionine is an intermediate in the synthesis of cysteine.
Cystathionine is produced by the transsulfuration pathway which converts homocysteine into cystathionine. Cystathionine is then used by the enzymes cystathionine gamma-lyase (CTH), ...
into
cysteine,
2-oxobutanoate (
α-ketobutyrate), and
ammonia
Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous wa ...
:
:
L-cystathionine + H
2O =
L-cysteine + 2-oxobutanoate + NH
3 (overall reaction)
::(1a)
L-cystathionine =
L-cysteine + 2-aminobut-2-enoate
::(1b) 2-aminobut-2-enoate = 2-iminobutanoate (spontaneous)
::(1c) 2-iminobutanoate + H
2O = 2-oxobutanoate + NH
3 (spontaneous)
Pyridoxal phosphate
Pyridoxal phosphate (PLP, pyridoxal 5'-phosphate, P5P), the active form of vitamin B6, is a coenzyme in a variety of enzymatic reactions. The International Union of Biochemistry and Molecular Biology has catalogued more than 140 PLP-dependent a ...
is a
prosthetic group
A prosthetic group is the non-amino acid component that is part of the structure of the heteroproteins or conjugated proteins, being tightly linked to the apoprotein.
Not to be confused with the cofactor that binds to the enzyme apoenzyme (eith ...
of this enzyme.
Cystathionine γ-lyase also
catalyses the following elimination reactions:
*
L-
homoserine
Homoserine (also called isothreonine) is an α-amino acid with the chemical formula HO2CCH(NH2)CH2CH2OH. -Homoserine is not one of the common amino acids encoded by DNA. It differs from the proteinogenic amino acid serine by insertion of an additi ...
to form H
2O, NH
3 and 2-oxobutanoate
*
L-
cystine
Cystine is the oxidized derivative of the amino acid cysteine and has the formula (SCH2CH(NH2)CO2H)2. It is a white solid that is poorly soluble in water. As a residue in proteins, cystine serves two functions: a site of redox reactions and a mec ...
, producing thiocysteine,
pyruvate and NH
3
*
L-
cysteine producing pyruvate, NH
3 and H
2S
In some
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typically a few micrometr ...
and
mammals, including humans, this enzyme takes part in generating
hydrogen sulfide.
Hydrogen sulfide is one of a few gases that was recently discovered to have a role in
cell signaling
In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...
in the body.
Enzyme mechanism
Cystathionase uses pyridoxal phosphate to facilitate the cleavage of the sulfur-gamma carbon bond of cystathionine, resulting in the release of cysteine.
The
lysine residue reforms the internal
aldimine
In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bon ...
by kicking off α-iminobutyric acid. Afterwards the external
ketimine
In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon– nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional si ...
is hydrolyzed, causing the formation of α-ketobutyrate.
The amino group on cystathionine is
deprotonated
Deprotonation (or dehydronation) is the removal (transfer) of a proton (or hydron, or hydrogen cation), (H+) from a Brønsted–Lowry acid in an acid–base reaction.Henry Jakubowski, Biochemistry Online Chapter 2A3, https://employees.csbsju.ed ...
and undergoes a
nucleophilic attack
In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...
of the internal aldimine. An additional deprotonation by a
general base results in the formation of the external aldimine and removal of the lysine residue. The basic lysine residue is then able to deprotonate the alpha carbon, pushing electron density into the nitrogen of the
pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom. It is a highly flammable, weakly alkaline, water-miscible liquid with a ...
ring.
Pyridoxal phosphate is necessary to stabilize this
carbanionic intermediate; otherwise the proton's
pKa would be too high.
The beta carbon is then deprotonated, creating an
alpha-beta unsaturation and pushing a
lone pair onto the aldimine nitrogen. To reform the aldimine, this lone pair pushes back down, cleaving the sulfur-gamma carbon bond, resulting in the release of cysteine.
A pyridoxamine derivative of vinyl
glyoxylate
Glyoxylic acid or oxoacetic acid is an organic compound. Together with acetic acid, glycolic acid, and oxalic acid, glyoxylic acid is one of the C2 carboxylic acids. It is a colourless solid that occurs naturally and is useful industrially.
Str ...
remains after the gamma
elimination. The lone pair from the pyridine nitrogen pushes electron density to the gamma carbon, which is protonated by lysine. Lysine then attacks the external aldimine, pushing electron density to the beta carbon, which is protonated by a general acid. The imine is then
hydrolyzed to release α-ketobutyrate. Deprotonation of the lysine residue causes ammonia to leave, thus completing the
catalytic cycle
In chemistry, a catalytic cycle is a multistep reaction mechanism that involves a catalyst. The catalytic cycle is the main method for describing the role of catalysts in biochemistry, organometallic chemistry, bioinorganic chemistry, materials s ...
.
Cystathionine gamma lyase also shows gamma-synthase activity depending on the concentrations of reactants present.
The mechanisms are the same until they diverge after formation of the vinyl glyoxylate derivative. In the gamma synthase mechanism, the gamma carbon is attacked by a sulfur nucleophile, resulting in the formation of a new sulfur-gamma carbon bond.
Enzyme structure
Cystathionine γ-lyase is a member of the Cys/Met metabolism PLP-dependent enzymes family. Other members include cystathionine γ synthase, cystathionine β lyase, and methionine γ lyase.
It is also a member of the broader
aspartate aminotransferase
Aspartate transaminase (AST) or aspartate aminotransferase, also known as AspAT/ASAT/AAT or (serum) glutamic oxaloacetic transaminase (GOT, SGOT), is a pyridoxal phosphate (PLP)-dependent transaminase enzyme () that was first described by Arthur ...
family.
Like many other PLP-dependent enzymes, cystathionine γ-lyase is a
tetramer
A tetramer () ('' tetra-'', "four" + '' -mer'', "parts") is an oligomer formed from four monomers or subunits. The associated property is called ''tetramery''. An example from inorganic chemistry is titanium methoxide with the empirical formula ...
with
D2 symmetry.
Pyridoxal phosphate is bound in the active site by Lys
212.
Disease relevance
![Cystathionase inhibited zoomed](https://upload.wikimedia.org/wikipedia/commons/e/e6/Cystathionase_inhibited_zoomed.png)
Cysteine is the
rate-limiting substrate in the synthetic pathway for
glutathione
Glutathione (GSH, ) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, pe ...
in the eye. Glutathione is an
antioxidant that protects
crystallins in the eye from reactive oxygen species; denatured crystallins can lead to
cataracts
A cataract is a cloudy area in the lens of the eye that leads to a decrease in vision. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colors, blurry or double vision, halos around light, trouble w ...
. Cystathionase is also a target for reactive oxygen species. Thus as cystathionase is oxidized, its activity decreases, causing a decrease in cysteine and, in turn, glutathione in the eye, leading to a decrease in antioxidant availability, causing a further decrease in cystathionase activity. Deficiencies in cystathionase activity have also been shown to contribute to glutathione depletion in patients with
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
and
AIDS.
Mutations and deficiencies in cystathionase are associated with
cystathioninuria
Cystathioninuria, also called cystathionase deficiency, is an autosomal recessive metabolic disorder. It is characterized by an abnormal accumulation of plasma cystathionine leading to excess cystathionine in the urine. Hereditary cystathioninuria ...
. The mutations T67I and Q240E weaken the enzyme's affinity for pyridoxal phosphate, the co-factor vital to enzymatic function.
Low levels of H
2S have also been associated with
hypertension in mice.
![Propargylglycine](https://upload.wikimedia.org/wikipedia/commons/9/9e/Propargylglycine.jpg)
Excessive levels of H
2S, due to increased activity of cystathionase, are associated with
endotoxemia
Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer m ...
,
acute pancreatitis
Acute pancreatitis (AP) is a sudden inflammation of the pancreas. Causes in order of frequency include: 1) a gallstone impacted in the common bile duct beyond the point where the pancreatic duct joins it; 2) heavy alcohol use; 3) systemic disea ...
,
hemorrhagic shock
Hypovolemic shock is a form of shock caused by severe hypovolemia (insufficient blood volume or extracellular fluid in the body). It could be the result of severe dehydration through a variety of mechanisms or blood loss. Hypovolemic shock is a m ...
, and
diabetes mellitus
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
.
Propargylglycine and
β-cyanoalanine are two
irreversible inhibitors of cystathionase used to treat elevated H
2S levels. Mechanistically, the amino group of propargylglycine attacks the
aldimine
In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bon ...
to form an external aldimine. The β position of the alkyne is then deprotonated to form the
allene
In organic chemistry, allenes are organic compounds in which one carbon atom has double bonds with each of its two adjacent carbon centres (). Allenes are classified as cumulated dienes. The parent compound of this class is propadiene, which ...
, which is then attacked by the phenol of
Tyr114. The internal aldimine can regenerate, but the newly created vinyl ether
sterically hinders the active site, blocking cysteine from attacking pyridoxal phosphate.
Regulation
H
2S decreases
transcription
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, the fir ...
of cystathionase at concentrations between 10 and 80μM. However, transcription is increased by concentrations near 120μM, and inhibited completely at concentrations in excess of 160μM.
See also
*
Cysteine metabolism
Cysteine metabolism refers to the biological pathways that consume or create cysteine. The pathways of different amino acids and other metabolites interweave and overlap to creating complex systems.cysteine is metabolism creating complex systems
...
References
External links
*
{{Portal bar, Biology, border=no
EC 4.4.1