Serine dehydratase or
L-serine ammonia lyase (SDH) is in the β-family of
pyridoxal phosphate-dependent (PLP) enzymes. SDH is found widely in nature, but its structural and properties vary among species. SDH is found in
yeast
Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to constitut ...
, bacteria, and the
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
of mammalian
hepatocytes
A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass.
These cells are involved in:
* Protein synthesis
* Protein storage
* Transformation of carbohydrates
* Synthesis of cholesterol, b ...
. SDH catalyzes is the
deamination
Deamination is the removal of an amino group from a molecule. Enzymes that catalyse this reaction are called deaminases.
In the human body, deamination takes place primarily in the liver, however it can also occur in the kidney. In situations of e ...
of
L-serine to yield
pyruvate
Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell.
Pyruvic aci ...
, with the release of
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 was ...
.
This enzyme has one
substrate,
L-serine, and two
product
Product may refer to:
Business
* Product (business), an item that serves as a solution to a specific consumer problem.
* Product (project management), a deliverable or set of deliverables that contribute to a business solution
Mathematics
* Produ ...
s,
pyruvate
Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell.
Pyruvic aci ...
and
NH3, and uses one
cofactor,
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 ac ...
(PLP). The enzyme's main role is in
gluconeogenesis
Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrat ...
in the
liver's cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
.
Nomenclature
Serine Dehydratase is also known as:
* L-serine ammonia-lyase
* Serine deaminase
* L-hydroxyaminoacid dehydratase
* L-serine deaminase
* L-serine dehydratase
* L-serine hydro-lyase
Structure
The
holoenzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as product (ch ...
SDH contains 319
residue
Residue may refer to:
Chemistry and biology
* An amino acid, within a peptide chain
* Crop residue, materials left after agricultural processes
* Pesticide residue, refers to the pesticides that may remain on or in food after they are applied ...
s, one
PLP cofactor molecule.
The overall fold of the
monomer
In chemistry, a monomer ( ; ''mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or three-dimensional network in a process called polymerization.
Classification
Mo ...
is very similar to that of other
PLP-dependent enzymes of the Beta-family. The enzyme contains a large
catalytic
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
domain
Domain may refer to:
Mathematics
*Domain of a function, the set of input values for which the (total) function is defined
**Domain of definition of a partial function
**Natural domain of a partial function
**Domain of holomorphy of a function
* Do ...
that binds
PLP and a small domain. The domains are linked by two residues 32-35 and 138-146, with the internal gap created being the space for the
active site
In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) a ...
Cofactor Binding
The
PLP cofactor is positioned in between the
Beta-strands 7 and 10 of the large domain and lies on the large internal gap made between small and large domain. The cofactor is
covalently
A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atoms ...
bonded through a
Schiff base linkage to
Lys41. The cofactor is sandwiched between the side chain of
Phe40 and the main chain of
Ala222. Each of the polar substituents of PLP is coordinated by functional groups: the
pyridinium
Pyridinium refers to the cation . It is the conjugate acid of pyridine. Many related cations are known involving substituted pyridines, e.g. picolines, lutidines, collidines. They are prepared by treating pyridine with acids.
As pyridine is oft ...
nitrogen of PLP is hydrogen-bonded to the side chain of
Cys303, the C3-hydroxyl group of PLP is hydrogen-bonded to the side chain of
Asn67, and the
phosphate group
In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid .
The phosphate or orthophosphate ion is derived from phosphor ...
of PLP is coordinated by main chain amides from the tetraglycine loop.
(Figure 3 and Figure 4).
Mechanism
The
reaction
Reaction may refer to a process or to a response to an action, event, or exposure:
Physics and chemistry
*Chemical reaction
*Nuclear reaction
*Reaction (physics), as defined by Newton's third law
*Chain reaction (disambiguation).
Biology and me ...
catalyzed by serine dehydratase follows the pattern seen by other PLP-dependent reactions. A
Schiff base linkage is made and the aminoacrylate group is released which undergoes non-enzymatic hydrolytic deamination to
pyruvate
Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell.
Pyruvic aci ...
.
Inhibitors
According to the series of assays performed by Cleland (1967), the linear rate of
pyruvate
Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell.
Pyruvic aci ...
formation at various
concentrations
In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', ''molar concentration'', ''number concentration'', an ...
of inhibitors demonstrated that L-
cysteine
Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, sometime ...
and D-
serine
Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...
competitively inhibit the enzyme SDH. The reason that SDH activity is
inhibited by L-cysteine is because an
inorganic sulfur is created from L-
Cysteine
Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, sometime ...
via Cystine Desulfrase and sulfur-containing groups are known to promote inhibition. L-threonine competitively inhibits Serine Dehydratase as well.
Moreover, insulin is known to accelerate
glycolysis
Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...
and repress induction of liver serine dehydratase in adult
diabetic
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 app ...
rats. Studies have been conducted to show
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
causes a 40-50% inhibition of the induction serine dehydratase by
glucagon
Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medicati ...
in
hepatocytes
A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass.
These cells are involved in:
* Protein synthesis
* Protein storage
* Transformation of carbohydrates
* Synthesis of cholesterol, b ...
of rats. Studies have also shown that
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
and
epinephrine
Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...
inhibit Serine Dehydratase activity by inhibiting
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 the SDH gene in the hepatocytes. Similarly, increasing levels of
glucagon
Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medicati ...
, increase the activity of SDH because this
hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
up-regulates the SDH enzyme. This makes sense in the context of
gluconeogenesis
Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrat ...
. The main role of SDH is to create
pyruvate
Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell.
Pyruvic aci ...
that can be converted into free glucose. And
glucagon
Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medicati ...
gives the signal to repress gluconeogenesis and increase the amount of free glucose in the blood by releasing glycogen stores from the liver.
Homocysteine
Homocysteine is a non-proteinogenic α-amino acid. It is a homologue of the amino acid cysteine, differing by an additional methylene bridge (-CH2-). It is biosynthesized from methionine by the removal of its terminal Cε methyl group. In the b ...
, a compound that SDH combines with Serine to create
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), cy ...
, also noncompetitively inhibits the action of SDH. Studies have shown that homocysteine reacts with SDH's PLP coenzyme to create a complex. This complex is devoid of coenzyme activity and SDH is not able to function (See Enzyme Mechanism Section).
In general, homocysteine is an amino acid and metabolite of
methionine
Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical ro ...
; increased levels of homocysteine can lead to
homocystinuria
Homocystinuria or HCU is an inherited disorder of the metabolism of the amino acid methionine due to a deficiency of cystathionine beta synthase or methionine synthase. It is an inherited autosomal recessive trait, which means a child needs to inh ...
(see section Disease Relevance).
Biological function
In general, SDH levels decrease with increasing mammalian size.
SDH enzyme plays an important role in gluconeogenesis. Activity is augmented by
high-protein diet
A high-protein diet is a diet in which 20% or more of the total daily calories comes from protein.Longe, Jacqueline L. (2008). ''High-protein diet''. In ''The Gale Encyclopedia of Diets: A Guide to Health and Nutrition''. Gale. pp. 524-526. Most ...
s and starvation. During periods of low
carbohydrates
In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may or may ...
, serine is converted into pyruvate via SDH. This pyruvate enters the
mitochondria
A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
where it can be converted into
oxaloacetate
Oxaloacetic acid (also known as oxalacetic acid or OAA) is a crystalline organic compound with the chemical formula HO2CC(O)CH2CO2H. Oxaloacetic acid, in the form of its conjugate base oxaloacetate, is a metabolic intermediate in many processes ...
, and, thus, glucose.
Little is known about the properties and the function of human SDH because human liver has low SDH activity. In a study done by Yoshida and Kikuchi, routes of glycine breakdown were measured. Glycine can be converted into serine and either become pyruvate via serine dehydratase or undergo
oxidative
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...
cleavage into
methylene-THF,
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 was ...
, and carbon dioxide. Results showed the secondary importance of the SDH pathway.
Disease relevance
SDH may be significant in the development of
hyperglycemia
Hyperglycemia is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a blood sugar level higher than 11.1 mmol/L (200 mg/dL), but symptoms may not start to become noticeable until even ...
and tumors.
Nonketotic hyperglycemia
Hyperglycemia is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a blood sugar level higher than 11.1 mmol/L (200 mg/dL), but symptoms may not start to become noticeable until even ...
is due to the deficiency of
threonine dehydratase, a close relative of serine dehydratase. Serine dehydratase has also been found to be absent in human
colon carcinoma
Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel m ...
and rat
sarcoma
A sarcoma is a malignant tumor, a type of cancer that arises from transformed cells of mesenchymal (connective tissue) origin. Connective tissue is a broad term that includes bone, cartilage, fat, vascular, or hematopoietic tissues, and sarcom ...
. The observed enzyme imbalance in these tumors shows that an increased capacity for the synthesis of serine is coupled to its utilization for
nucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules wi ...
biosynthesis as a part of the commitment to
cellular replication in cancer cells. This pattern is found in
sarcomas
A sarcoma is a malignant tumor, a type of cancer that arises from transformed cells of mesenchymal (connective tissue) origin. Connective tissue is a broad term that includes bone, cartilage, fat, vascular, or hematopoietic tissues, and sarcoma ...
and
carcinomas
Carcinoma is a malignancy that develops from epithelial cells. Specifically, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that arises from cells originating in the endodermal, mesoderm ...
, and in tumors of human and rodent origin.
Evolution
Human and rat serine dehydratase
cDNA
In genetics, complementary DNA (cDNA) is DNA synthesized from a single-stranded RNA (e.g., messenger RNA (mRNA) or microRNA (miRNA)) template in a reaction catalyzed by the enzyme reverse transcriptase. cDNA is often used to express a speci ...
are identical except for a 36 amino acid residue stretch. Similarities have also been shown between yeast and ''E. coli''
threonine dehydratase and human serine dehydratase. Human SDH shows sequence homology of 27% with the yeast enzyme and 27% with the E. coli enzyme.
Overall PLP enzymes exhibit high conservation of the active site residues.
External links
*
References
{{reflist, 2