Burstyn Group
Bioinorganic Chemistry at the University of Wisconsin
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Cystathionine β-synthase
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| The enzyme cystathionine β-synthase (CBS) catalyzes the condensation of serine and homocysteine to produce cystathionine, an important intermediate in the biosynthesis of cysteine. Deficiency of CBS activity results in toxic levels of homocysteine and is the most common cause of homocystinuria, a disease whose symptoms include dislocated eye lenses, skeletal and vascular problems, and mental retardation. Mammalian CBS is a unique heme protein that requires the cofactor pyridoxal 5'-phosphate (PLP). Although heme is essential for activity in mammalian CBS, the chemistry is performed by PLP, and heme is not present in the enzyme of lower organisms. Why, then, has nature included a heme in the CBS of mammals? Our hypothesis is that the heme of CBS is acting as a regulator of enzyme activity. A number of studies demonstrate that there is communication between the heme and the active site, e.g. small molecule binding and reduction of the heme both diminish enzyme activity. In collaboration with Professor Jan Kraus (University of Colorado, Denver), we are currently probing the enzyme and the heme with a variety of spectroscopic and biochemical methods, such as electronic absorption and magnetic circular dichroism (MCD), and resonance Raman spectroscopies, site-directed mutagenesis, and radiochemical enzyme assays in an attempt to unlock the mystery of the heme in this enzyme. |
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The crystal structure of human CBS reveals a dimer with heme and PLP cofactors (boxed, right).
The regions of the enzyme which we think stabilize the heme are shaded in red.
The CBS heme is six-coordinate with the amino acids histidine and cysteine
serving as axial ligands (upper left). This type of heme coordination is very
rare and may be responsible for the unique properties of the CBS heme. |
