Page last updated: 2024-10-24

keratan sulfate biosynthetic process

Definition

Target type: biologicalprocess

The chemical reactions and pathways resulting in the formation of keratan sulfate, a glycosaminoglycan with repeat units consisting of beta-1,4-linked D-galactopyranosyl-beta-(1,4)-N-acetyl-D-glucosamine 6-sulfate and with variable amounts of fucose, sialic acid and mannose units; keratan sulfate chains are covalently linked by a glycosidic attachment through the trisaccharide galactosyl-galactosyl-xylose to peptidyl-threonine or serine residues. [ISBN:0198547684, RESID:AA0247]

Keratan sulfate (KS) biosynthesis is a complex and tightly regulated process that involves the stepwise assembly of a unique glycosaminoglycan (GAG) chain attached to a core protein. The process takes place primarily in the Golgi apparatus of cells and is essential for the formation of various tissues and organs. Here's a detailed breakdown:

**1. Core Protein Synthesis:**

* KS biosynthesis begins with the synthesis of a core protein. These proteins are typically transmembrane or secreted proteins found in various tissues, including cartilage, cornea, and bone.
* Common core proteins include aggrecan (in cartilage), lumican (in cornea), and keratocan (in cornea).
* The core protein contains specific amino acid sequences (typically serine or threonine residues) that act as attachment sites for the KS chain.

**2. Initiation of KS Chain Formation:**

* The first step in KS chain assembly is the transfer of a xylose residue from UDP-xylose to the core protein. This reaction is catalyzed by xylosyltransferase I (XYLT1).
* The addition of xylose to the core protein sets the stage for the subsequent addition of galactose residues.

**3. Galactose Addition:**

* A galactose residue is then added to the xylose by galactosyltransferase I (GalT1), forming a xylose-galactose disaccharide.
* This disaccharide serves as a foundation for the elongation of the KS chain.

**4. N-Acetylglucosamine Addition:**

* The next step involves the transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to the galactose residue. This is catalyzed by N-acetylglucosaminyltransferase I (GlcNAcT1).
* This creates a trisaccharide unit (xylose-galactose-GlcNAc), which represents the repeating disaccharide unit of the KS chain.

**5. Elongation of the KS Chain:**

* The trisaccharide unit serves as a primer for the further elongation of the KS chain.
* The process involves the alternating addition of galactose and GlcNAc residues to the growing chain.
* These additions are catalyzed by a series of specific galactosyltransferases (GalTs) and N-acetylglucosaminyltransferases (GlcNAcTs).

**6. Sulfation of KS Chains:**

* Once the KS chain reaches a certain length, sulfation occurs.
* Sulfation is catalyzed by specific sulfotransferases (STs) that transfer sulfate groups from 3'-phosphoadenosine-5'-phosphosulfate (PAPS) to specific hydroxyl groups on the galactose and GlcNAc residues.
* Sulfation patterns are highly diverse and vary depending on the tissue and the specific KS chain.
* Sulfation is critical for the proper function of KS and contributes to its structural integrity and interaction with other molecules.

**7. Diversity in KS Chains:**

* KS chains exhibit significant structural diversity due to variations in chain length, sulfation patterns, and branching.
* This diversity allows KS to fulfill a variety of roles in different tissues.

**8. Role of KS in Tissues:**

* KS is a major component of the extracellular matrix (ECM) in various tissues.
* In cartilage, KS contributes to the resilience and elasticity of the tissue, aiding in its ability to withstand compressive forces.
* In cornea, KS is crucial for maintaining the transparency and refractive index of the eye.
* In bone, KS plays a role in regulating bone growth and development.

**9. Regulation of KS Biosynthesis:**

* KS biosynthesis is tightly regulated, ensuring the production of the correct type and amount of KS in each tissue.
* Regulation occurs at multiple levels, including the expression of core proteins, glycosyltransferases, sulfotransferases, and other enzymes involved in the pathway.
* Factors that influence regulation include developmental stage, tissue type, and environmental stimuli.

**10. Diseases Associated with KS Biosynthesis:**

* Defects in KS biosynthesis can lead to various diseases, including:
* **Corneal dystrophies:** Mutations in genes encoding KS-related enzymes can cause corneal clouding and visual impairment.
* **Skeletal dysplasias:** Defects in KS synthesis can affect cartilage development and lead to skeletal abnormalities.
* **Other disorders:** Disruptions in KS biosynthesis may contribute to other diseases, including cancer and inflammation.

**In summary, KS biosynthesis is a complex process that involves the assembly of a unique GAG chain attached to a core protein. This process is essential for the formation and function of various tissues and organs, and defects in KS biosynthesis can lead to a range of diseases.**
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Proteins (2)

ProteinDefinitionTaxonomy
CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 1A CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q11201]Homo sapiens (human)
CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 1A CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q11201]Homo sapiens (human)

Compounds (11)

CompoundDefinitionClassesRoles
2,3-dihydroxybenzoic acid2,3-dihydroxybenzoic acid : A dihydroxybenzoic acid that is benzoic acid substituted by hydroxy groups at positions 2 and 3. It occurs naturally in Phyllanthus acidus and in the aquatic fern Salvinia molesta.

2,3-dihydroxybenzoic acid: RN given refers to parent cpd

dihydroxybenzoic acid : Any member of the class of hydroxybenzoic acids carrying two phenolic hydroxy groups on the benzene ring and its derivatives.
dihydroxybenzoic acidhuman xenobiotic metabolite;
plant metabolite
protocatechuic acid3,4-dihydroxybenzoic acid : A dihydroxybenzoic acid in which the hydroxy groups are located at positions 3 and 4.

protocatechuic acid: RN given refers to parent cpd; structure
catechols;
dihydroxybenzoic acid
antineoplastic agent;
EC 1.1.1.25 (shikimate dehydrogenase) inhibitor;
EC 1.14.11.2 (procollagen-proline dioxygenase) inhibitor;
human xenobiotic metabolite;
plant metabolite
gallic acidgallate : A trihydroxybenzoate that is the conjugate base of gallic acid.trihydroxybenzoic acidantineoplastic agent;
antioxidant;
apoptosis inducer;
astringent;
cyclooxygenase 2 inhibitor;
EC 1.13.11.33 (arachidonate 15-lipoxygenase) inhibitor;
geroprotector;
human xenobiotic metabolite;
plant metabolite
beta-resorcylic acidbeta-resorcylic acid: RN given refers to parent cpd; structure
2,5-dihydroxybenzoic acid2,5-dihydroxybenzoic acid : A dihydroxybenzoic acid having the two hydroxy groups at the 2- and 5-positions.

2,5-dihydroxybenzoic acid: RN given refers to parent cpd; a oxidative product of saligenin
dihydroxybenzoic acidEC 1.13.11.33 (arachidonate 15-lipoxygenase) inhibitor;
fungal metabolite;
human metabolite;
MALDI matrix material;
mouse metabolite
veratric acid3,4-dimethoxybenzoic acid : A member of the class of benzoic acids that is benzoic acid substituted by methoxy groups at positions 2 and 3.

veratric acid: RN given refers to parent cpd; structure
benzoic acidsallergen;
plant metabolite
methyl gallatemethyl 3,4,5-trihydroxybenzoate : A gallate ester obtained by the formal condensation of gallic acid with methanol. It exhibits anti-oxidant, anti-tumor, anti-microbial and anti-inflammatory properties.

methyl gallate: has both immunosuppressive and phytogenic antineoplastic activities; isolated from Acer saccharinum
gallate esteranti-inflammatory agent;
antioxidant;
plant metabolite
3,4,5-trimethoxybenzoic acid3,4,5-trimethoxybenzoic acid : A benzoic acid derivative carrying 3-, 4- and 5-methoxy substituents.

3,4,5-trimethoxybenzoic acid: RN given refers to parent cpd; structure
benzoic acids;
methoxybenzenes
human urinary metabolite;
human xenobiotic metabolite;
plant metabolite
syringic acidsyringic acid : A dimethoxybenzene that is 3,5-dimethyl ether derivative of gallic acid.

syringic acid: RN given refers to parent cpd; structure in third source
benzoic acids;
dimethoxybenzene;
phenols
plant metabolite
epigallocatechin gallate(-)-epigallocatechin 3-gallate : A gallate ester obtained by the formal condensation of gallic acid with the (3R)-hydroxy group of (-)-epigallocatechin.

epigallocatechin gallate: a steroid 5alpha-reductase inhibitor and antimutagen in green tea (Camellia sinensis)
flavans;
gallate ester;
polyphenol
antineoplastic agent;
antioxidant;
apoptosis inducer;
geroprotector;
Hsp90 inhibitor;
neuroprotective agent;
plant metabolite
guanosine diphosphateGuanosine Diphosphate: A guanine nucleotide containing two phosphate groups esterified to the sugar moiety.guanosine 5'-phosphate;
purine ribonucleoside 5'-diphosphate
Escherichia coli metabolite;
mouse metabolite;
uncoupling protein inhibitor