ACAA1

ACAA1 Full Name

acetyl-CoA acyltransferase 1

ACAA1 Introduction

Acetyl-CoA acyltransferase 1 (ACAA1), widely known in the scientific community as peroxisomal 3-oxoacyl-CoA thiolase, is a vital metabolic enzyme predominantly localized within the peroxisomes of mammalian cells. Synthesized in the cytoplasm and subsequently transported into the peroxisomal matrix, ACAA1 functions as a cornerstone of cellular lipid metabolism, operating as a functional homodimer to execute complex biochemical reactions. The primary physiological role of ACAA1 lies in its catalysis of the final, thiolytic cleavage step of the peroxisomal beta-oxidation cycle. Specifically, it cleaves 3-ketoacyl-CoA to produce acetyl-CoA and a chain-shortened acyl-CoA. This enzymatic activity is absolutely indispensable for the degradation of specific lipid molecules that are too complex, long, or bulky to be processed directly by mitochondria. Most notably, ACAA1 is required for the breakdown of very-long-chain fatty acids (VLCFAs) and certain branched-chain fatty acids. By facilitating the conversion of these robust lipids into shorter fragments that can subsequently be exported to the mitochondria for complete oxidation, ACAA1 acts as a crucial gatekeeper for cellular lipid and energy homeostasis.

Figure 1. Comparison of peroxisomal and mitochondrial fatty acid βoxidation pathways. (Source: Schrader M, et al. 2015)

Clinically, the severe consequences of ACAA1 dysfunction highlight its biological importance. Genetic mutations leading to a functional deficiency of ACAA1 result in a rare, severe autosomal recessive peroxisomal disorder historically referred to as pseudo-Zellweger syndrome (isolated peroxisomal 3-oxoacyl-CoA thiolase deficiency). Patients with this condition suffer from the toxic systemic accumulation of VLCFAs, presenting clinically with profound hypotonia, severe developmental delays, progressive neurological decline, and early lethality. Beyond rare inborn errors of metabolism, ACAA1 is increasingly recognized for its role in oncology. Altered ACAA1 expression has been documented in malignancies such as hepatocellular carcinoma, breast cancer, and glioma, where tumor cells hijack and reprogram peroxisomal lipid metabolism to sustain rapid proliferation, resist oxidative stress, and fuel metastasis.

Alternate Names for ACAA1

ACAA1; acetyl-CoA acyltransferase 1; acetyl Coenzyme A acyltransferase 1; 3-ketoacyl-CoA thiolase, peroxisomal; peroxisomal 3 oxoacyl Coenzyme A thiolase; beta-ketothiolase; peroxisomal 3-oxoacyl-CoA thiolase; acetyl-Coenzyme A acyltransferase 1; peroxisomal 3-oxoacyl-Coenzyme A thiolase; ACAA

• 1. Schrader M, et al. Peroxisome-mitochondria interplay and disease. J Inherit Metab Dis. 2015 Jul;38(4):681-702.
  2. Wanders RJ, et al. Biochemistry of mammalian peroxisomes revisited. Annu Rev Biochem. 2006;75:295-332.