Amiya Hajra, PhD.
Research Professor, MBNI
Professor, Department of Biological Chemistry

MBNI Labs at Medical Science Research Bldg. II
1150 W. Medical Center Drive
Ann Arbor, MI 48109-0669

akhajra@umich.edu

(734) 763-4369

Hajra LB:
4424 Med Sci I 0606

Current Research Interests:

Lipid Synthesis in Peroxisomes

Our research has explored the mechanics and function of a phospholipid called acyl dihydroxyacetone phosphate (acyl DHAP). Our work has revealed that acyl DHAP plays a notable role in cell physiology and certain genetic disorders with far-reaching implications for human and animal biology. Our studies on the metabolism of acyl DHAP led to the discovery of a new lipid biosynthetic pathway, a novel biochemical reaction for the synthesis of ether bond in lipids, an unexpected subcellular site (peroxisomes) for lipid biogenesis in cells and the nature of biochemical defects in a number of genetic diseases involving peroxisomal disorders.

Acyl DHAP was discovered as a trace radioactive lipid formed when liver mitochondria were incubated with 32P-labeled ATP. We found that this lipid is synthesized via enzymatic acylation of DHAP by long chain acyl coenzyme A. Acyl DHAP was then shown to be reduced by NADPH to lysophosphatidic acid, the precursor of all cellular lipids (Ref.1). This is an alternate pathway, as opposed to the glycerophosphate pathway, for the synthesis of glycerolipids (Fig.1).

Fig.1. Acyl Dihydroxyacetone Phosphate Pathway for Lipid Synthesis.

We discovered that acyl DHAP is also the precursor of glycerol ether lipids in all animals (Ref.1). Acyl DHAP was found to react with a long chain alcohol to alkyl DHAP, an ether lipid (Fig.1). Glycerol ether lipids, such plasmalogens, are major component of lipids of excitable tissues such as brain, nerves, heart and muscle. The biochemical reaction by which acyl DHAP is converted to the ether lipid alkyl DHAP (Fig.1) is very unusual and recent studies indicate that oxidation-reduction reactions are involved in this reaction (Ref.2).

Fig.2. Topography of Acyl Dihydroxyacetone Phosphate Pathway Enzymes
in Peroxisomes.

Studies on the subcellular distribution of the acyl DHAP pathway enzymes have revealed that all these enzymes are present in peroxisomes of animal cells (Fig. 2). Peroxisomes are subcellular 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 cerebrohepatorenal syndrome (Fig.3), the tissues of the patients are deficient in ether lipids. We have shown that this was due to the absence of the peroxisomal enzyme, which catalyzes the synthesis of acyl DHAP (Ref.3). In these genetic diseases the patients suffer from neurological disorders, dismyelination and mental retardation.

Fig. 3. Zellweger CHRS patient.

We have recently shown that during the conversion of preadipocytes to adipocytes, two enzymes of the acyl DHAP pathway are highly induced thus leading to the increased synthesis of triglycerides, the storage lipid (Ref.4). This finding indicates that this pathway is important not only for the synthesis of ether lipids but also for the synthesis of non-ether lipids.

Selected Publications:

1. Hajra, A. K. (1995) Glycerolipid biosynthesis in peroxisomes (microbodies). Prog. Lipid Res. 34: 343-364.
2. Hajra, A. K. (2002) Peroxisomal acyl dihydroxyacetone phosphate pathway for glycerolipid biosynthesis. In Lipids: Glycerolipid Metabolizing Enzymes (Ed. D. Haldar and S. K. Das) Research Signpost, Trivandrum. Pp 55 – 66.
3. Datta, N. S., Wilson, G. N. and Hajra, A. K. (1984) Deficiency of enzymes catalyzing the biosynthesis of glycerol ether lipids in Zellweger syndrome. New Eng. J. Med. 311: 1080-1083.
4. Hajra, A. K., Larkins, L. K., Das, A. K., Hemati, N., Erickson, R. L. and MacDougald, O. A. (2000). Induction of the peroxisomal glycerolipid-synthesizing enzymes during differentiation of 3T3-L1 preadipocytes to adipocytes. J. Biol. Chem. 275: 9441-46.