D-Bifunctional Protein Deficiency
Encyclopedia
D-Bifunctional protein deficiency (officially called 17-β-hydroxysteroid dehydrogenase) is an autosomal
recessive peroxisomal
fatty acid oxidation disorder
. Peroxisomal disorder
s are usually caused by a combination of peroxisomal assembly defects or by deficiencies of specific peroxisomal enzyme
s. The peroxisome
is an organelle in the cell similar to the lysosome
that functions to detoxify the cell. Peroxisomes contain many different enzymes, such as catalase
, and their main function is to neutralize free radicals and detoxify drugs, such as alcohol. For this reason peroxisomes are ubiquitous in the liver and kidney. D-BP deficiency is the most severe peroxisomal disorder , often resembling Zellweger syndrome
.
Characteristics of the disorder include neonatal hypotonia
and seizures, occurring mostly within the first month of life, as well as visual and hearing impairment . Other symptoms include severe craniofacial disfiguration, psychomotor delay, and neuronal migration defects. Most onsets of the disorder begin in the gestational weeks of development and most affected individuals die within the first two years of life.
Type I deficient patients showed a large structural modification to the D-BP as a whole. Most of these individuals showed either a deletion or an insertion resulting in a frameshift mutation
. Type II and III patients showed small scale changes in the overall structure of D-BP[6]. Amino acid changes in the catalytic domains or those in contact with substrate or cofactors were the main cause of these variations of D-BP deficiency. Other amino acid changes were seen to alter the dimerization of the protein, leading to improper folding. Many mutations have been found in the gene coding for D-BP(HSD17B4
)on the q arm two of chromosome five (5q2) in Homo sapiens, most notably individuals homozygous for a missense mutation
(616S).
The DBP protein (79kDa) also known as “multifunctional protein 2”, “multifunctional enzyme 2”, or “D-peroxisomal bifunctional enzyme”, catalyzes the second and third steps of peroxisomal β-oxidation of fatty acids and their derivatives .
A non-functional D-BP protein results in the abnormal accumulation of long chain fatty acids and bile acid intermediates. The D-BP protein contains a peroxisomal targeting signal 1 (PTS1) unit at the C-terminus allowing for its transport into peroxisomes by the PTS1 receptor. Inside the peroxisomes, the D-BP protein is partially cleaved exclusively between the SDR and hydratase domains.
DBP is a stereospecific enzyme; hydratase domain forms only (R)-hydroxy-acyl-CoA intermediates from trans-2-enoyl-CoAs . D-BP is expressed throughout the entire human body, with the highest mRNA levels in the liver and brain. The hydrogenase and hydratase units of DBP exist as dimers, necessary for correct folding and therefore function of the enzyme.
is regulated at 400 basepairs upstream of the transcription start site .
The missense mutation G16S is the most common mutation that leads to D-BP deficiency. In a 2006 study in which 110 patients were tested, 28 suffered from this frameshift mutation. The second most frequent mutation was the missense mutation N457Y which was seen in 13 of the 110 patients. Type I patients showed only deletions, insertions, and nonsense mutations were identified, most leading to shortened polypeptides. Most type II patients show missense mutations in D-BP hydratase unit as well as some in-frame deletions. Type III individuals commonly show missense mutations in the coding region of the dehydrogenase domain.
, as shown in the G16S mutation. Glycine 16 forms a short loop and creates a hole for the adenine ring of NAD+ to enter. Other amino acid side chains alter the shape of this loop due to steric hindrance, and prevent proper NAD+ binding. Other mutations that exist are due to incorrect polypeptide folding. L405 (leucine located at residue 405) located in the substrate binding domain of the hydratase 2 unit, plays an important role in binding CoA ester moiety. One mutation seen in D-BP deficiency patients is caused by a leucine to proline substitution. This breaks the hydrophobic interactions necessary for proper substrate binding with CoA esters.
synthesis. Recent studies in D-BP knockout mice show compensatory upregulation of other peroxisomal enzymes in absence of D-BP such as palmitoyl-CoA oxidase, peroxisomal thiolase, and branched chain acyl-CoA oxidase .
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
recessive peroxisomal
Peroxisome
Peroxisomes are organelles found in virtually all eukaryotic cells. They are involved in the catabolism of very long chain fatty acids, branched chain fatty acids, D-amino acids, polyamines, and biosynthesis of plasmalogens, etherphospholipids critical for the normal function of mammalian brains...
fatty acid oxidation disorder
Fatty-acid metabolism disorder
A broad classification for genetic disorders that result from an inability of the body to produce or utilize one enzyme that is required to oxidize fatty acids. The enzyme can be missing or improperly constructed resulting in it not working...
. Peroxisomal disorder
Peroxisomal disorder
Peroxisomal disorders represent a class of medical conditions caused by defects in peroxisome functions. This may be due to defects in single enzymes important for peroxisome function or in peroxins, proteins encoded by PEX genes that are critical for normal peroxisome assembly and...
s are usually caused by a combination of peroxisomal assembly defects or by deficiencies of specific peroxisomal enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s. The peroxisome
Peroxisome
Peroxisomes are organelles found in virtually all eukaryotic cells. They are involved in the catabolism of very long chain fatty acids, branched chain fatty acids, D-amino acids, polyamines, and biosynthesis of plasmalogens, etherphospholipids critical for the normal function of mammalian brains...
is an organelle in the cell similar to the lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
that functions to detoxify the cell. Peroxisomes contain many different enzymes, such as catalase
Catalase
Catalase is a common enzyme found in nearly all living organisms that are exposed to oxygen, where it catalyzes the decomposition of hydrogen peroxide to water and oxygen...
, and their main function is to neutralize free radicals and detoxify drugs, such as alcohol. For this reason peroxisomes are ubiquitous in the liver and kidney. D-BP deficiency is the most severe peroxisomal disorder , often resembling Zellweger syndrome
Zellweger syndrome
Zellweger syndrome, also called cerebrohepatorenal syndrome is a rare, congenital disorder, characterized by the reduction or absence of functional peroxisomes in the cells of an individual. It is one of a family of disorders called leukodystrophies...
.
Characteristics of the disorder include neonatal hypotonia
Hypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
and seizures, occurring mostly within the first month of life, as well as visual and hearing impairment . Other symptoms include severe craniofacial disfiguration, psychomotor delay, and neuronal migration defects. Most onsets of the disorder begin in the gestational weeks of development and most affected individuals die within the first two years of life.
Classification
DBP deficiency can be divided into three types:- type I, characterized by a deficiency in both the hydratase and dehydrogenase units of D-BP
- type II, in which only the hydratase unit is non-functional
- type III, with only a deficiency in the dehydrogenase unit
Type I deficient patients showed a large structural modification to the D-BP as a whole. Most of these individuals showed either a deletion or an insertion resulting in a frameshift mutation
Frameshift mutation
A frameshift mutation is a genetic mutation caused by indels of a number of nucleotides that is not evenly divisible by three from a DNA sequence...
. Type II and III patients showed small scale changes in the overall structure of D-BP[6]. Amino acid changes in the catalytic domains or those in contact with substrate or cofactors were the main cause of these variations of D-BP deficiency. Other amino acid changes were seen to alter the dimerization of the protein, leading to improper folding. Many mutations have been found in the gene coding for D-BP(HSD17B4
HSD17B4
Peroxisomal multifunctional enzyme type 2 is a protein that in humans is encoded by the HSD17B4 gene.-Further reading:...
)on the q arm two of chromosome five (5q2) in Homo sapiens, most notably individuals homozygous for a missense mutation
Missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide is changed, resulting in a codon that codes for a different amino acid . This can render the resulting protein nonfunctional...
(616S).
D-BP Protein
The D-bifunctional protein is composed of three enzymatic domains: the N-terminal short chain alcohol dehydrogenase reductase (SDR), central hydratase domain, and the C-terminal sterol carrier protein 2 (SDR) .The DBP protein (79kDa) also known as “multifunctional protein 2”, “multifunctional enzyme 2”, or “D-peroxisomal bifunctional enzyme”, catalyzes the second and third steps of peroxisomal β-oxidation of fatty acids and their derivatives .
A non-functional D-BP protein results in the abnormal accumulation of long chain fatty acids and bile acid intermediates. The D-BP protein contains a peroxisomal targeting signal 1 (PTS1) unit at the C-terminus allowing for its transport into peroxisomes by the PTS1 receptor. Inside the peroxisomes, the D-BP protein is partially cleaved exclusively between the SDR and hydratase domains.
DBP is a stereospecific enzyme; hydratase domain forms only (R)-hydroxy-acyl-CoA intermediates from trans-2-enoyl-CoAs . D-BP is expressed throughout the entire human body, with the highest mRNA levels in the liver and brain. The hydrogenase and hydratase units of DBP exist as dimers, necessary for correct folding and therefore function of the enzyme.
Genetic
The D-BP gene (HSD17B4), found on the long arm of chromosome 5, consists of 24 exons and 23 introns and is over 100kb in size. Exons 1-12 code for the SDR domain, 12-21 for the hydratase domain, and 21-24 for the SCP2 domain. TranscriptionTranscription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
is regulated at 400 basepairs upstream of the transcription start site .
The missense mutation G16S is the most common mutation that leads to D-BP deficiency. In a 2006 study in which 110 patients were tested, 28 suffered from this frameshift mutation. The second most frequent mutation was the missense mutation N457Y which was seen in 13 of the 110 patients. Type I patients showed only deletions, insertions, and nonsense mutations were identified, most leading to shortened polypeptides. Most type II patients show missense mutations in D-BP hydratase unit as well as some in-frame deletions. Type III individuals commonly show missense mutations in the coding region of the dehydrogenase domain.
Chemistry
Enzymatic activity of D-BP fails if the protein cannot effectively bind the cofactor NAD+Nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved...
, as shown in the G16S mutation. Glycine 16 forms a short loop and creates a hole for the adenine ring of NAD+ to enter. Other amino acid side chains alter the shape of this loop due to steric hindrance, and prevent proper NAD+ binding. Other mutations that exist are due to incorrect polypeptide folding. L405 (leucine located at residue 405) located in the substrate binding domain of the hydratase 2 unit, plays an important role in binding CoA ester moiety. One mutation seen in D-BP deficiency patients is caused by a leucine to proline substitution. This breaks the hydrophobic interactions necessary for proper substrate binding with CoA esters.
Diagnosis
The most common clinical observations of patients suffering from D-bifunctional protein deficiency include hypotonia, facial and skull dysmorphism, neonatal seizures, and neuronal demyelination. High levels of branched fatty acids, such as pristinic acid, bile acid intermediates, and other D-BP substrates are seen to exist. Reduced pristinic acid β-oxidation is a common indicator of D-BP deficiency . D-BP can be distinguished from Zellweger Syndrome by normal plasmalogenPlasmalogen
Plasmalogens are a type of ether phospholipid characterized by the presence of a vinyl ether linkage at the sn-1 position and an ester linkage at the sn-2 position . In mammals, the sn-1 position is typically derived from C16:0, C18:0, or C18:1 fatty alcohols while the sn-2 position is most...
synthesis. Recent studies in D-BP knockout mice show compensatory upregulation of other peroxisomal enzymes in absence of D-BP such as palmitoyl-CoA oxidase, peroxisomal thiolase, and branched chain acyl-CoA oxidase .