Professor Emeritus, Biological Chemistry
B.Sc., M.Sc., Calcutta University
Ph.D., Northwestern University
Postdoctoral, University of Michigan
Research Profile
Our research centers on the mechanism and control of phospholipid biogenesis at the enzymic and genetic levels and also the role of phospholipids in signal transduction across biological membranes.
We are studying lipid biosynthesis via the acyl dihydroxyacetone phosphate (acyl DHAP) pathway. Acyl DHAP is a trace lipid present in all animal tissues and we have found it to be an important precursor for membrane glycerol ether lipids which are highly concentrated in excitable tissues such as brain, nerves and muscles. Acyl DHAP, formed from enzymatic acylation of DHAP, is converted to the ether lipid alkyl DHAP by a novel biochemical displacement of the acyl group by a long chain alcohol. Alkyl DHAP is then reduced by NADPH to form the ether analog of lysophosphatidate, which is the precursor of all glycerol ether lipids, including plasmalogens. The membrane-bound enzymes of the acyl DHAP pathway have been solubilized and purified in our and other laboratories and recently their cDNA's have been cloned. Active recombinant enzymes have been expressed in E. coli and we have used them to study their catalytic mechanisms and to raise specific antibodies to help identify the native enzymes and also to study the transcriptional and translational controls of their biogenesis under different physiological conditions. Recent findings indicate that not only ether lipids but cellular non-ether glycerolipids are also synthesized via the acyl DHAP pathway.
We have also shown, surprisingly, that the enzymes of the acyl DHAP pathway for lipid synthesis are not present in endoplasmic reticulum (the site of most lipid biosynthetic enzymes) but in peroxisomes. Peroxisomes are organelles present in all eukaryotes, but their function was, until recently, unknown. Our work and reports from other laboratories have now established that a major function of peroxisomes is to regulate cellular lipid metabolism. The obligatory role of peroxisomes in ether lipid biogenesis has been confirmed by the finding that in genetic diseases involving peroxisomal disorders, such as in Zellweger syndrome, the tissues of the patients are deficient in ether lipids. This is apparently due to the absence of the peroxisomal enzyme that catalyzes the synthesis of acyl DHAP. We are in the process of studying the possible molecular defects (mutations) in acyl DHAP pathway enzymes that cause some of these genetic diseases.
We are also involved in studying the generation and metabolism of lipid second messengers, such as diacylglycerol (DAG), in biological signal transduction. We have developed a method for quantitative molecular species analysis of DAG to differentiate among its various cellular roles. Using this method, we have shown that following receptor activation both inositol and choline-containing lipids break down to form DAG. However, the DAG formed from inositol lipids is recycled back to the parent lipids, while the DAG from choline-containing lipids is not recycled. The physiological function and the mechanism of recycling of the large amount of DAG formed after chronic receptor activation are currently being studied in our laboratory.
Publications
Das, A.K., Horie, S., and Hajra, A.K. (1992) Biosynthesis of Glycerolipid Precursors in Rat Liver Peroxisomes and their Transport and Conversion to Phosphatidate in the Endoplasmic Reticulum. J. Biol. Chem. 267:9724-9730.
PMID: 1577808
Lee, C., and Hajra, A. K. (1993) Quantitative analysis of changes in the molecular species of glycerolipids in cultured cells during signal transduction. Neuroprotocols 3, 83-90.
Webber, K.O. and Hajra, A.K. (1993) Purification and properties of dihydroxyacetone phosphate acyltransferase. Meth. Enzymol. 209, 92-98.
Hajra, A.K. (1995) Glycerolipid biosynthesis in peroxisomes. Progr. in Lipid Research 34, 343-364. PMID: 8685243
Broustas, C. Larkins, L.K. Uhler, M.D. and Hajra, A.K. (1997) Molecular cloning and expression of cDNA encoding rat brain cytosolic acyl coenzyme A thioester hydrolase. J. Biol. Chem. 271, 10470-10476.
Hajra A.K. and Das A. K. (1996) Lipid biosynthesis in peroxisomes. Annal. N. Y. Acad. Sci. 804, 129-141. PMID: 8993541
Hajra A. K. (1997) Dihydroxyacetone phosphate acyltransferase. Biochim. Biophys. Acta. 1348, 27-34. PMID: 9370313