Figure 1

Cholesterol catabolism pathways. (a) Cholesterol catabolism pathway in Actinomycetes. Mycobacterium tuberculosis and some species of Rhodococcus have the capacity to catabolize cholesterol as a source of carbon and energy. In these strains, two catabolic pathways have been identified. One (step 1) is the side chain degradation pathway, in which the aliphatic side chain on C-17 is removed in a process similar to beta-oxidation. The second is the four-ring degradation pathway (steps 2–8). In ring degradation, three enzymes, cholesterol-3-OH-dehydrogenase (step 2), 3-ketosteroid Δ¹-dehydrogenase (step 3), and 3-ketosteroid-9α-hydroxylase (step 4) catalyze B-ring opening and A-ring aromatization to produce 3-hydroxy-9,10-seconandrost-1,3,5(10)-triene-9,17-dione (3-HSA). Three additional enzymes (HasAB, step 5; HasC, step 6; HasD; step 7) then generate 9,17-dioxo-1,2,3,4,10,19-hexanorandrostan-5-oic acid (DOHNAA) via oxygenolytic cleavage of ring A. (b) Theoretical pathway for cholesterol catabolism in humans. Steroidogenic cells express cytochrome p450s that can remove the C-17 side chain during steroid hormone biosynthesis (step 1). However, humans lack enzymes needed to degrade the cyclopentanoperhydrophenanthrene (cholestane) ring. To allow B ring opening in human cells we humanized cholesterol-3-OH-dehydrogenase (CholD; to catalyze step 2), 3-ketosteroid Δ¹-dehydrogenase (Δ¹-KstD; to catalyze step 3) and 3-ketosteroid-9α-hydroxylase (Kst-9αH; to catalyze step 4). Brackets designate unstable intermediate compounds that degrade spontaneously. Abbreviations: DHEA, 3β-hydroxyandrost-5-ene-17-one; AD, androst-4-ene-3,17-dione; ADD, androsta-1,4-diene-3,17-dione; 3,4-DHSA, 3,4-dihydroxy-9,10-seconandrost-1,3,5(10)-triene-9,17-dione; 4,9-DSHA, 4,5–9,10-diseco-3-hydroxy-5,9,17-trioxoandrosta-1(10),2-diene-4-oic acid; DOHNAA, 9,17-dioxo-1,2,3,4,10,19-hexanorandrostan-5-oic acid; PL, 3β-hydroxypregn-5-en-20-one; PD, pregn-4-ene-3,20-dione; PDD, pregn-1,4-diene-3,20-dione; 3-HSP, 3-hydroxy-9,10-secopregn-1,3,5(10)-triene-9,20-dione; 9-OHPDD, 9-hydroxypregn-1,4-diene-3,20-dione. The pathways in part A are based, in part, on the studies of Van der Geize et al.⁵³.